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WO2016105484A1 - Derivatives of 5-(hetero)arylpyrazol-3-carboxylic amide or 1-(hetero)aryltriazol-4-carboxylic amide useful for the treatment of inter alia cystic fibrosis - Google Patents

Derivatives of 5-(hetero)arylpyrazol-3-carboxylic amide or 1-(hetero)aryltriazol-4-carboxylic amide useful for the treatment of inter alia cystic fibrosis Download PDF

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Publication number
WO2016105484A1
WO2016105484A1 PCT/US2015/000211 US2015000211W WO2016105484A1 WO 2016105484 A1 WO2016105484 A1 WO 2016105484A1 US 2015000211 W US2015000211 W US 2015000211W WO 2016105484 A1 WO2016105484 A1 WO 2016105484A1
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optionally substituted
group
alkyl
compound
cftr
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PCT/US2015/000211
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French (fr)
Inventor
Cecilia M. Bastos
Benito Munoz
Bradley Tait
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Proteostasis Therapeutics, Inc.
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Priority to CA2971855A priority Critical patent/CA2971855A1/en
Priority to US15/539,401 priority patent/US10738011B2/en
Publication of WO2016105484A1 publication Critical patent/WO2016105484A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6872—Intracellular protein regulatory factors and their receptors, e.g. including ion channels
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/38—Pediatrics
    • G01N2800/382—Cystic fibrosis

Definitions

  • Protein homeostasis a balance between protein synthesis, folding, trafficking, aggregation, and degradation, referred to as protein homeostasis, utilizing sensors and networks ofpathways (Sitia et al., Nature 426: 891 -894, 2003; Ron et & ⁇ ., Nat Rev Mol Cell Biol 8: 519- 529, 2007).
  • the cellular maintenance of protein homeostasis, or proteostasis refers to controlling the conformation, binding interactions, location and concentration of individual proteins making up the proteome.
  • Protein folding in vivo is accomplished through interactions between the folding polypeptide chain and macromolecular cellular components, including multiple classes of chaperones and folding enzymes, which minimize aggregation (Wiseman et al., Cell 131: 809-821 , 2007). Whether a given protein folds in a certain cell type depends on the distribution, concentration, and subcellular localization of chaperones, folding enzymes, metabolites and the like (Wiseman et al.). Cystic fibrosis and other maladies of protein misfolding arise as a result of an imbalance in the capacity of the protein homeostasis
  • Cystic Fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene which encodes a multi-membrane spanning epithelial chloride channel (Riordan et al., Annu Rev Biochem 11, 701-26 (2008)). Approximately ninety percent of patients have a deletion of phenylalanine (Phe) 508 (AF508) on at least one allele.
  • CFTR cystic fibrosis transmembrane conductance regulator
  • This mutation results in disruption of the energetics of the protein fold leading to degradation of CFTR in the endoplasmic reticulum (ER).
  • ER endoplasmic reticulum
  • the AF508 mutation is thus associated with defective folding and trafficking, as well as enhanced degradation of the mutant CFTR protein (Qu et al., J Biol Chem 272, 15739-44 (1997)).
  • the loss of a functional CFTR channel at the plasma membrane disrupts ionic homeostasis (CF, Na + , HCO 3 " ) and airway surface hydration leading to reduced lung function (Riordan et al.).
  • the present disclosure is based, in part, on the discovery that disclosed compounds can increase cystic fibrosis transmembrane conductance regulator (CFTR) activity as measured in human bronchial epithelial (hBE) cells.
  • CTR cystic fibrosis transmembrane conductance regulator
  • hBE human bronchial epithelial
  • Xi is CH or N; wherein when Xi is N, R z is not present and the nitrogen with R z has a double bond with the adjacent N and there is a single bond between Xi and the adjacent N, and when Xi is CH, Xi has a double bond with the nitrogen adjacent, and R z is selected from the group consisting of H, and Ci-3alkyl, and the nitrogen with R z has a single bond with the adjacent N;
  • X 3 is selected from the group consisting of O, S, and NRht,;
  • Ri i is independently selected for each occurrence from the group consisting of hydrogen, halogen, C ⁇ alkyl (optionally substituted by one, two or three halogens);
  • Li is selected from the group consisting of Ci-6 alkylene, C3.6 cycloalkylene, C 3- 6cycloalkylene-Ci. 4 alkylene, Ci -3 alkylene-NR hh -S(0) w-i - Ci -3 alkylene-S(0) w -NRhh-, C 3 .
  • Li may be optionally substituted by one, two or three substituents selected from the group consisting of halogen, hydroxyl, C] -3alkyl (optionally substituted by one, two or three substituents each selected independently from R f r);
  • R4 4 is selected from the group consisting of H, halogen, hydroxyl, Ci -3 alkoxy, heterocycle, and a 5-6 membered monocyclic or 8-10 membered bicyclic heteroaryl having one, two or three heteroatoms each selected from O, N, and S; wherein the heterocycle and the heteroaryl may be optionally substituted by one or two substituents each selected independently from R gg ;
  • R f r is selected for each occurrence from group consisting of halogen, hydroxyl, Ci- 4 alkyl, C, -4 alkyoxy, C 2 . 4 alkenyl, C 3-6 cycloalkyl, -NR'R", -NR'-S(0) w -Ci -3 alkyl, S(0) w -
  • Ci -4 alkyl, C )-4 alkyoxy, C 2-4 alkenyl and C 3 .6cycloalkyl may be optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, -NR'R", -NR'-S(0) w - C, -3 alkyl, S(0) w -NR'R", and -SiO d ⁇ alkyl;
  • R gg is selected for each occurrence from group consisting of halogen, hydroxyl, C ⁇ .
  • C 2- 6alkenyl and C 3- 6cycloalkyl may each be optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, Ci-6alkoxy, hydroxyl, C(0)OH, -C(0)OC )-6 alkyl, -0-C 3-6 cycloalkyl, -O-heterocycle, -O-heteroaryl, -O-phenyl, - NR'R", -NR'-S(0) w -C,. 3 alkyl, S(0) w -NR'R", and -S(0)w-C,. 3 alkyl, S(0) w -NR'R", and -S(0)w-C,. 3 alkyl, S(0) w -NR'R", and -S(0)w-C,. 3 alkyl, S(0) w -NR'R", and -S(0)w-C,. 3 alkyl, S(0) w -NR'R", and -S(0)w-
  • w 0, 1 or 2;
  • R hh is selected for each occurrence from the group consisting of H, Ci.6alkyl and C 3- 6cycloalkyl.
  • pharmaceutical compositions that include a disclosed compound such as those compounds having Formula (IVa), (Va), (IV), or (V) and a pharmaceutically acceptable carrier or excipient.
  • the compositions can include at least one additional CFTR modulator as described anywhere herein or at least two additional CFTR modulators, each independently as described anywhere herein.
  • a method of enhancing (e.g., increasing) cystic fibrosis transmembrane conductance regulator (CFTR) activity in a subject in need thereof comprising administering to said subject an effective amount of a compound of Formula (IVa), (Va), (IV), or (V).
  • CFTR cystic fibrosis transmembrane conductance regulator
  • the activity of one or more (e.g., one or two) mutant CFTRs is enhanced (e.g., increased).
  • one or more mutant CFTRs e.g., AF508, S549N, G542X, G551D, Rl 17H, N1303K, W1282X, R553X, 621+1 G>T, 1717-1G>A, 3849+l OkbOT, 2789+5G>A, 3120+1OA, I507del, R1 162X, 1898+1 G>A, 3659delC, G85E, Dl 152H, R560T, R347P, 2184insA, A455E, R334W, Q493X, and 2184delA CFTR) is enhanced (e.g., increased).
  • AF508 CFTR activity is enhanced (e.g., increased).
  • the activities of two mutant CFTRs e.g., AF508 and G551D; AF508 and A455E; or G542X; A508F are enhanced (e.g., increased).
  • the subject e.g., a human patient
  • a disease associated with decreased CFTR activity e.g., cystic fibrosis, congenital bilateral absence of vas deferens (CBAVD), acute, recurrent, or chronic pancreatitis, disseminated bronchiectasis, asthma, allergic pulmonary aspergillosis, chronic obstructive pulmonary disease (COPD), chronic sinusitis, dry eye disease, protein C deficiency, ⁇ - ⁇ -lipoproteinemia, lysosomal storage disease, type 1 chylomicronemia, mild pulmonary disease, lipid processing deficiencies, type 1 hereditary angioedema, coagulation-fibrinolyis, hereditary
  • CBAVD congenital bilateral absence of vas deferens
  • COPD chronic obstructive pulmonary disease
  • COPD chronic sinusitis
  • dry eye disease protein C deficiency
  • ⁇ - ⁇ -lipoproteinemia lysosomal
  • hemochromatosis CFTR-related metabolic syndrome
  • chronic bronchitis constipation
  • pancreatic insufficiency hereditary emphysema
  • Sjogren's syndrome familial
  • hypercholesterolemia I-cell disease/pseudo-Hurler, mucopolysaccharidoses, Sandhof/Tay- Sachs, Crigler-Najjar type II, polyendocrinopathy/hyperinsulemia, Diabetes mellitus, Laron dwarfism, myleoperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1 , congenital hyperthyroidism, osteogenesis imperfecta, hereditary
  • the disease is cystic fibrosis.
  • the disclosure is directed to treating a patient suffering from cystic fibrosis comprising administering to said patient an effective amount of a disclosed compound.
  • the methods described herein can further include
  • At least one CFTR modulator is a CFTR corrector (e.g., VX-809, VX-661 , VX-983, VX-152, VX-440, GLPG2222 and GLPG2665) or potentiator (e.g., ivacaftor and genistein).
  • CFTR corrector e.g., VX-809, VX-661 , VX-983, VX-152, VX-440, GLPG2222 and GLPG2665
  • potentiator e.g., ivacaftor and genistein
  • one of the at least two additional therapeutic agents is a CFTR corrector (e.g., VX-809, VX-661 , VX-983, VX-152, VX-440, GLPG2222 and GLPG2665) and the other is a CFTR potentiator (e.g., ivacaftor and genistein).
  • CFTR corrector e.g., VX-809, VX-661 , VX-983, VX-152, VX-440, GLPG2222 and GLPG2665
  • a CFTR potentiator e.g., ivacaftor and genistein
  • a method of identifying a candidate agent that increases CFTR activity includes: (i) contacting a cell that expresses a CFTR protein with the candidate agent and a disclosed compound; (ii) measuring the CFTR activity in the cell in the presence of the candidate agent and the disclosed compound; and (iii) comparing the CFTR activity to that in the absence of the test agent, wherein an increase in CFTR activity in the presence of the test agent indicates that the agent increases CFTR activity.
  • the cell expresses a mutant CFTR protein.
  • CFTR activity is measured by measuring chloride channel activity of the CFTR, and/or other ion transport activity.
  • the method is high-throughput.
  • the candidate agent is a CFTR corrector or a CFTR potentiator.
  • the words “a” and “an” are meant to include one or more unless otherwise specified.
  • the term “an agent” encompasses both a single agent and a combination of two or more agents.
  • the present disclosure is directed in part to compounds as described herein having the Formula (IV) or (V), or a pharmaceutically acceptable salt, prodrug or solvate thereof, pharmaceutical compositions, methods of increasing CFTR activity and methods of treating cystic fibrosis.
  • Xi is CH or N; wherein when Xi is N, R z is not present and the nitrogen with R z has a double bond with the adjacent N and there is a single bond between Xi and the adjacent N, and when Xi is CH, Xi has a double bond with the nitrogen adjacent, and R z is selected from the group consisting of H, and Ci-3alkyl, and the nitrogen with R z has a single bond with the adjacent N;
  • X 3 is selected from the group consisting of O, S, and NRhh;
  • pp is 1 , 2, or 3;
  • Ri 1 is independently selected for each occurrence from the group consisting of hydrogen, halogen, Ci -4 alkyl (optionally substituted by one, two or three halogens);
  • Li is selected from the group consisting of Ci. 6 alkylene, C3.6 cycloalkylene, C 3- alkylene, Ci -3 alkylene-NRhh-S(0) w-j - Ci-3 alkylene-S(0) w -NRhh-, C 3- 6 cycloalkylene-Co -2 alkylene-S(0) w -NRhh, and C3-6 cycloalkylene- Co -2 alkylene NRhh-S(0) w-; wherein Li may be optionally substituted by one, two or three substituents selected from the group consisting of halogen, hydroxyl, Ci-3alkyl (optionally substituted by one, two or three substituents each selected independently from R f j);
  • R44 is selected from the group consisting of H, halogen, hydroxyl,
  • heterocycle and a 5-6 membered monocyclic or 8-10 membered bicyclic heteroaryl having one, two or three heteroatoms each selected from O, N, and S; wherein the heterocycle and the heteroaryl may be optionally substituted by one or two substituents each selected independently from R gg ;
  • R f r is selected for each occurrence from group consisting of halogen, hydroxyl, C ⁇ . 4 alkyl, C alkyoxy, C 2 . 4 alkenyl, C 3-6 cycloalkyl, -NR'R", -NR'-S(0) w -Ci -3 alkyl, S(0) w - NR'R", and -S(0) w -Ci -3 alkyl, where w is 0, 1 , or 2, wherein Ci -4 alkyl, Ci -4 alkyoxy, C 2- 4alkenyl and C 3- 6cycloalkyl may be optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, -NR'R", -NR'-S(0) w - C 1-3 alkyl, S(0) w -NR'R", and -S(0) w -Ci -3 alkyl;
  • R gg is selected for each occurrence from group consisting of halogen, hydroxyl, Ci. ealkyl, C 1-6 alkyoxy, C 2-6 alkenyl, C 3-6 cycloalkyl, -NR'R", -NR'-S(0) w -Ci -3 alkyl, S(0) w - NR'R", and -S(0) w -Ci.3alkyl, where w is 0, 1 , or 2, wherein Ci -6 alkyl, d -6 alkyoxy, C 2-6 alkenyl and C3- 6 cycloalkyl may each be optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, Ci-ealkyl, Ci-ealkoxy, hydroxyl, C(0)OH, -C(0)OCi -6 alkyl, -0-C 3-6 cycloalkyl, -O-heterocycle, -O-heteroaryl, -O-pheny
  • w 0, 1 or 2;
  • R hh is selected for each occurrence from the group consisting of H, Ci -6 alkyl and C 3 . 6 cycloalkyl.
  • Li may be Ci -3 alkylene or C 3-5 cycloalkylene and/or Xi is CH or C.
  • R44 of one or more of above formulas is selected from the group consisting of: pyrrolidinyl, piperidinyl, tetrahydropyranyl, and tetrahydrofuranyl. In other embodiments, R44 is selected from the group consisting of:
  • X independently for each occurrence is selected from the group consisting of O, S, NR hh , C, C(Rsg), and C(Rg8)(R99);
  • X 2 independently for each occurrence is selected from the group consisting of O, S and NR hh ;
  • R" is H or C ]-4 alkyl, each R66, R77, ss and R99 is independently selected for each occurrence from H and R gg , and n is 0, 1, 2, or 3.
  • each R66, R77, ss and R99 is independently selected for each occurrence from the group consisting of hydrogen, halogen, hydroxyl, Ci-6 alkyl, C 3- 6 cycloalkyl, and heterocycle, wherein Ci -6 alkyl, C 3- 6 cycloalkyl, and heterocycle are optionally substituted by one, two or three substituents each independently selected from the group consisting of hydroxyl, Ci -6 alkyl, Ci ⁇ alkoxy (optionally substituted by C3 -6 cycloalkyl, heterocycle, -Ci_ 2 alkyl-heterocycle and Ci -2 alkyl- C 3- 6cycloalkyl), -S(0) w -Ci -3 alkyl (w is 0, 1 , or 2) and -NR'S(0) 2 Ci-6 alkyl; and R' is independently selected for each occurrence from H and Ci-4 alkyl and/or pp is 0, 1 or 2, and Ri 1 is selected from H, F, or
  • Ri is selected from the group consisting of:
  • R 2 is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl;
  • R 3a is selected from the group consisting of hydrogen, optionally substituted CpCio alkyl, optionally substituted C 2 -Ci 0 alkenyl, optionally substituted C 2 -Cio alkynyl, optionally substituted C 3 -Ci 2 cycloalkyl, optionally substituted C3-Ci 2 cycloalkenyl, optionally substituted aryl, halo, ORc, NRd j, C(0)ORc, N0 2 , CN, C(0)Rc, C(0)C(0)Rc, C(0)NRdRd, NRdC(0)Rc, NR d S(0)nRc, N(R d )(COORc), NR d C(0)C(0)Rc, NR d C(0)NR d R d , NRdS(0) admirNR «
  • R4b is selected from the group consisting of hydrogen, optionally substituted Ci-Ci 0 alkyl, optionally substituted C 2 -Cio alkenyl, optionally substituted C 2 -Cio alkynyl, optionally substituted C 3 -Ci 2 cycloalkyl, optionally substituted C 3 -C] 2 cycloalkenyl, optionally substituted aryl, optionally substituted heterocyclic and optionally substituted heteroaryl;
  • R a is selected from the group consisting of hydrogen, optionally substituted CpCio alkyl, optionally substituted C 2 -Ci 0 alkenyl, optionally substituted C 2 -Ci 0 alkynyl, optionally substituted CrCi 2 cycloalkyl, optionally substituted C3-Ci 2 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, C(0)ORc, C(0)Rc, C(0)C(0)Rc and S(0) n Rc;
  • Ra and the nitrogen atom to which it is attached is taken together with an adjacent C(R b i)(R b i) or C(Rb 2 )(Rb 2 ) to form an optionally substituted, 4- to 12-membered heterocyclic ring containing one or more ring nitrogen atoms, wherein said heterocyclic ring optionally contains one or more ring heteroatoms selected from oxygen and sulfur;
  • each Rbi and R 1 ⁇ 2 is independently selected from the group consisting of hydrogen, optionally substituted CpCio alkyl, optionally substituted C 2 -Cio alkenyl, optionally substituted C 2 -Cio alkynyl, optionally substituted C3-Ci 2 cycloalkyl, optionally substituted C3-Ci 2 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, ORc, NRjR d , C(0)ORc, N0 2 , CN, C(0)Rc, C(0)C(0)Rc,
  • Y is selected from the group consisting of S(0) n> , ⁇ 3 ⁇ 4, NR d S(0) n , NR d S(0) n NR d , NR d C(O), NR d C(0)0, NR ⁇ ,C(0)C(0), NR d C(0)NR d , S(0) n NR ⁇ ,, and O;
  • each Rc is independently selected from the group consisting of hydrogen, optionally substituted CpCio alkyl, optionally substituted C 2 -Ci 0 alkenyl, optionally substituted C 2 -Cio alkynyl, optionally substituted C 3 -Ci 2 cycloalkyl, optionally substituted C 3 -Ci 2 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;
  • each R d is independently selected from the group consisting of hydrogen, optionally substituted Ci-Cio alkyl, optionally substituted C 2 -Cio alkenyl, optionally substituted C 2 -Cio alkynyl, optionally substituted Ci-Cio alkoxy, optionally substituted C3-C12 cycloalkyl, optionally substituted C 3 -Ci 2 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl; or two geminal Ra groups are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic or an optionally substituted heteroaryl;
  • k is 0 or 1 ;
  • n 0, 1 , 2, 3, 4, or 5;
  • each n is independently 0, 1 or 2.
  • m is 0, 1 or 2 (e.g., m is 0 or m is 1). In some embodiments, k is 0. In some embodiments, m is 0, 1 or 2 (e.g., m is 0 or m is 1), and k is 0.
  • R 3a is hydrogen.
  • Ra is hydrogen or Ci-C 4 alkyl (optionally substituted by 1 , 2 or 3 halogens). In certain embodiments, R a is hydrogen.
  • Rbi and Rb 2 are each independently selected from the group consisting of hydrogen, hydroxyl, C ⁇ alkoxy (optionally substituted by one, two or three substituents independently selected from halogen and hydroxyl) and C1-C4 alkyl (optionally substituted by one, two or three substituents independently selected from halogen and hydroxyl).
  • R i and Rb 2 for each occurrence are hydrogen.
  • R 2 is selected from the group consisting of phenyl and a 5-6 membered heteroaryl having one or two heteroatoms each selected from N, S, and O, wherein R 2 is optionally substituted by one or two substituents each independently selected from the group consisting of halogen, and Ci-C 4 alkyl (optionally substituted by one, two or three halogens).
  • R 2 is phenyl. In other embodiments, R 2 is phenyl is substituted with one or two R 5j wherein each R 5 is independently selected from the group consisting of optionally substituted C1-C10 alkyl, optionally substituted C 2 -Ci 0 alkenyl, optionally substituted C 2 -Cio alkynyl, and halo. In still other embodiments, R 2 is a para- substituted phenyl. [0030] In other embodiments, R 2 is selected from the group consisting of: optionally substituted thienyl, optionally substituted furanyl and optionally substituted pyridinyl.
  • R 4a is selected from the group consisting of optionally substituted C r C 6 alkyl, optionally substituted C3-C7 cycloalkyl, phenyl, ORc, C(0)ORc, C(0)Rc, optionally substituted heterocycle and optionally substituted heteroaryl, wherein Rc is selected, independently for each occurrence, from the group consisting of H and Ci_6alkyl.
  • R4 a is heterocycle, or a 5-6 membered monocyclic or a 8- 10 membered bicyclic heteroaryl having one, two or three heteroatoms selected from N, S or O, wherein the heterocycle or heteroaryl are optionally substituted by one, two or three substituents independently selected for each occurrence from the group consisting of halogen, Ci. 6 alkyl (optionally substituted by one, two or three substituents each independently selected from halogen and hydroxyl), Ci -6 alkoxy (optionally substituted by one, two or three halogens), hydroxyl, and NR ⁇ Rd wherein R ⁇ is independently for each occurrence selected from H and Q.
  • R4 a can be selected from the group consisting of tetrahydropyranyl, thiadiazolyl, tetrahydrofuranyl, and morpholinyl.
  • R 4a can be a monocyclic heteroaryl containing one, two or three ring nitrogen atoms.
  • R a can be selected from the group consisting of furanyl, pyridinyl, pyrazinyl, pyrazolyl, imidazolyl, isoxazolyl, triazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, thienyl, piperazinyl, and
  • R 4a is selected from the group consisting of:
  • each X is independently O, S or NR g ;
  • each R g is independently selected from the group consisting of hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl;
  • each R6_ R 7 and R 8 is independently selected for each occurrence from the group consisting of hydrogen, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -Ci 6 alkynyl, C 3 -C 7 cycloalkyl, C3-C7 cycloalkenyl, phenyl, heterocycle, heteroaryl, halo, hydroxyl, carboxyl, ORc, NRdRd, C(0)ORc, CN, C(0)R c , wherein the Ci -6 alkyl, C 2 -C 6 alkenyl, C 2 -C 16 alkynyl, C 3 -C 7 cycloalkyl, C3-C7 cycloalkenyl, phenyl, heterocycle, and heteroaryl of R6, R7 and R 8 may each be optionally substituted by one, two or three substituents selected from halo, hydroxyl, Ci-6alkyl and Ci_ 6 alkoxy;
  • Rc is C alkyl
  • Rd is independently for each occurrence selected from the group consisting of H and Q. 4 alkyl, or the two RdS taken together with the N to which they are attached form a heterocyclic ring.
  • R ⁇ is an optionally substituted C3-C7 cycloalkyl (e.g., optionally substituted cyclopropyl or an optionally substituted cyclobutyl).
  • R4 a is substituted with a substituent having the
  • each Rh is independently selected for each occurrence from the group consisting of hydrogen, halo, hydroxyl, Ci-C 6 alkyl, and C3-C6 cycloalkyl, or two geminal Rh groups are independently taken together with the carbon atom to which they are attached to form an optionally substituted carbocyclic or heterocycle;
  • R9 is selected from the group consisting of hydrogen, halo, CN, hydroxyl, methyl (optionally substituted by one, two or three substituents selected from halogen and hydroxyl), C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, C ⁇ alkoxy, NR d Ra, C(0)ORc, N0 2 , CN,
  • Rc is independently selected for each occurrence from the group consisting of H, C1 -C6 alkyl, C3-6cycloalkyl, heterocycle, and heteroaryl;
  • R d is independently selected for each occurrence from H and C
  • R ⁇ can be selected from the group consisting of:
  • each Rio is independently selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C6 alkynyl, optionally substituted C3-C6 cycloalkyi, optionally substituted C3-C6 cycloalkenyl, optionally substituted aryl, halo, OR c , NRjR d , C(0)OR c , N0 2 , CN, C(0)R c , C(0)C(0)R c , C(0)NR d R d , NRdC(0)Rc, N3 ⁇ 4S(0) n Rc, NRd(COORc), NRdC(0)C(0)Rc, ⁇ 3 ⁇ 4 ⁇ (0) ⁇ 3 ⁇ 43 ⁇ 4, NR d S ⁇ n NR d R d , NR d S(0) precedeRc, S(0) n Rc, S(0) n NR ⁇ jR ⁇
  • Y is S, S(0) 2 or S(0) 2 NR d .
  • R4b is heterocycle or a 5-6 membered monocyclic or a 8-10 membered bicyclic heteroaryl having one, two or three heteroatoms selected from N, S or O, wherein the heterocycle or heteroaryl are optionally substituted by one, two or three substituents independently selected for each occurrence from the group consisting of halogen, Ci. 6 alkyl (optionally substituted by one, two or three substituents each independently selected from halogen and hydroxyl), Ci -6 alkoxy (optionally substituted by one, two or three halogens), hydroxyl, and NRdRd wherein Rd is independently for each occurrence selected from H and Q.
  • R4b can be selected from the group consisting of furanyl, pyridinyl, pyrazinyl, pyrazolyl, imidazolyl, isoxazolyl, triazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, thienyl, piperazinyl, and benzimidazolyl, each optionally substituted.
  • R4b can be selected from the group consisting of furanyl, pyridinyl, pyrazinyl, pyrazolyl, imidazolyl, isoxazolyl, triazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, thienyl, piperazinyl, and benzimidazolyl, each optionally substituted.
  • Exemplary compounds are shown below in Table 1 :
  • compositions that include a disclosed compound such as those compounds having Formula (IVa), (Va), (IV), or (V) and a pharmaceutically acceptable carrier or excipient.
  • the compositions can include at least one additional CFTR modulator as described anywhere herein or at least two additional CFTR modulators, each independently as described anywhere herein.
  • R 2a is fluoro
  • A is an optionally substituted imidazolyl or pyrazolyl.
  • the disclosure in an embodiment, thus encompasses compound of Formula (IVa), (Va), (IV), or (V), wherein R 2a is fluoro and A is an optionally substituted imidazolyl or pyrazolyl.
  • alkyl refers to both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; for example, "C r Cio alkyl” denotes alkyl having 1 to 10 carbon atoms, and straight or branched hydrocarbons of 1 -6, 1 -4, or 1 -3 carbon atoms, referred to herein as Ci_ 6 alkyl, and Q alkyl, respectively.
  • alkyl examples include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, 2- methylbutyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl, and 4-methylpentyl.
  • alkenyl refers to both straight and branched-chain moieties having the specified number of carbon atoms and having at least one carbon-carbon double bond.
  • Exemplary alkenyl groups include, but are not limited to, a straight or branched group of 2-6 or 3-4 carbon atoms, referred to herein as C2-6alkenyl, and C3 -4 alkenyl, respectively.
  • Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, etc.
  • alkynyl refers to both straight and branched-chain moieties having the specified number or carbon atoms and having at least one carbon-carbon triple bond.
  • cycloalkyl refers to saturated cyclic alkyl moieties having 3 or more carbon atoms, for example, 3-10, 3-6, or 4-6 carbons, referred to herein as C 3- l ocycloalkyl, C 3- 6cycloalkyl or C 4- 6cycloalkyl, respectively for example.
  • Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and adamantyl.
  • cycloalkenyl refers to cyclic alkenyl moieties having 3 or more carbon atoms.
  • cycloalkynyl refers to cyclic alkynyl moieties having 5 or more carbon atoms.
  • Alkylene means a straight or branched, saturated aliphatic divalent radical having the number of carbons indicated.
  • Cycloalkylene refers to a divalent radical of carbocyclic saturated hydrocarbon group having the number of carbons indicated.
  • alkoxy refers to a straight or branched alkyl group attached to oxygen (alkyl-O-).
  • exemplary alkoxy groups include, but are not limited to, alkoxy groups of 1 -6 or 2-6 carbon atoms, referred to herein as Ci-ealkoxy, and C 2 -6alkoxy,
  • heterocyclic or “heterocycle” encompasses heterocycloalkyl, heterocycloalkenyl, heterobicycloalkyl, heterobicycloalkenyl, heteropolycycloalkyl, heteropolycycloalkenyl, and the like unless indicated otherwise.
  • Heterocycloalkyl refers to cycloalkyl groups containing one or more heteroatoms (O, S, or N) within the ring.
  • Heterocycloalkenyl as used herein refers to cycloalkenyl groups containing one or more heteroatoms (O, S or N) within the ring.
  • Heterobicycloalkyl refers to bicycloalkyl groups containing one or more heteroatoms (O, S or N) within a ring.
  • Heterobicycloalkenyl as used herein refers to bicycloalkenyl groups containing one or more heteroatoms (O, S or N) within a ring.
  • a heterocycle can refer to, for example, a saturated or partially unsaturated 4- to 12 or 4- 10-membered ring structure, including bridged or fused rings, and whose ring structures include one to three heteroatoms, such as nitrogen, oxygen, and sulfur.
  • heterocyclic rings may be linked to the adjacent radical through carbon or nitrogen.
  • heterocyclic groups include, but are not limited to, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxetane, azetidine, tetrahydrofuran or dihydrofuran, etc.
  • Cycloalkyl, cycloalkenyl, and heterocyclic groups also include groups similar to those described above for each of these respective categories, but which are substituted with one or more oxo moieties.
  • aryl refers to mono- or polycyclic aromatic carbocyclic ring systems.
  • a polycyclic aryl is a polycyclic ring system that comprises at least one aromatic ring.
  • Polycyclic aryls can comprise fused rings, covalently attached rings or a combination thereof.
  • aryl embraces aromatic radicals, such as, phenyl, naphthyl, indenyl, tetrahydronaphthyl, and indanyl.
  • An aryl group may be substituted or unsubstituted.
  • the aryl is a C4-C10 aryl.
  • heteroaryl refers to aromatic carbocyclic groups containing one or more heteroatoms (O, S, or N) within a ring.
  • a heteroaryl group unless indicated otherwise, can be monocyclic or polycyclic.
  • a heteroaryl group may additionally be substituted or unsubstituted.
  • Heteroaryl groups can also include ring systems substituted with one or more oxo moieties.
  • a polycyclic heteroaryl can comprise fused rings, covalently attached rings or a combination thereof.
  • a polycyclic heteroaryl is a polycyclic ring system that comprises at least one aromatic ring containing one or more heteroatoms within a ring.
  • heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, triazinyl, isoindolyl, purinyl, oxadiazolyl, thiadiazoly
  • heteroaryl groups may be C-attached or heteroatom-attached (where such is possible).
  • a group derived from pyrrole may be pyrrol- 1-yl (N-attached) or pyrrol-3-yl (C-attached).
  • the heteroaryl is 4- to 12-membered heteroaryl.
  • the heteroaryl is a mono or bicyclic 4- to 10-membered heteroaryl.
  • substituted refers to substitution by independent replacement of one, two, or three or more of the hydrogen atoms with substituents including, but not limited to, and unless indicated otherwise, -Ci-Ci2 alkyl, -C 2 -Ci 2 alkenyl, -C 2 -Ci 2 alkynyl, -C3-Ci 2 cycloalkyl, -C 3 -C,2 cycloalkenyl, C 3 -C, 2 cycloalkynyl, -heterocyclic, -F, -CI, -Br, -I, -OH, -N0 2 , -N 3 , -CN, -NH 2 , oxo, thioxo, -NHR X , -NR X R X , dialkylamino, -diarylamino, -diheteroarylamino, -OR x
  • halo or halogen as used herein refer to F, CI, Br, or I.
  • haloalkyl refers to an alkyl group having 1 to (2n+l) substituent(s) independently selected from F, CI, Br or I, where n is the maximum number of carbon atoms in the alkyl group. It will be understood that haloalkyl is a specific example of an optionally substituted alkyl.
  • hydroxy and "hydroxyl” as used herein refers to the radical -OH.
  • the compounds of the disclosure may contain one or more double bonds and, therefore, exist as geometric isomers resulting from the arrangement of substituents around a carbon-carbon double bond.
  • the symbol denotes a bond that may be a single, double or triple bond as described herein.
  • Substituents around a carbon-carbon double bond are designated as being in the "Z” or configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the "E " and "Z” isomers.
  • Substituents around a carbon-carbon double bond alternatively can be referred to as "cis” or "trans,” where "cis” represents substituents on the same side of the double bond and "trans” represents substituents on opposite sides of the double bond.
  • Compounds of the disclosure may contain a carbocyclic or heterocyclic ring and therefore, exist as geometric isomers resulting from the arrangement of substituents around the ring.
  • the arrangement of substituents around a carbocyclic or heterocyclic ring are designated as being in the "Z” or “E " configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting carbocyclic or heterocyclic rings encompass both “Z” and “E” isomers.
  • Substituents around a carbocyclic or heterocyclic ring may also be referred to as “cis” or “trans”, where the term “cis” represents substituents on the same side of the plane of the ring and the term “trans” represents substituents on opposite sides of the plane of the ring.
  • cis/trans represents substituents on both the same and opposite sides of plane of the ring.
  • Individual enantiomers and diasterisomers of compounds of the present disclosure can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art.
  • Stereoselective syntheses a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a pre-existing one, are well known in the art.
  • Stereoselective syntheses encompass both enantio- and diastereoselective transformations, and may involve the use of chiral auxiliaries. For examples, see Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley- VCH: Weinheim, 2009. Where a particular compound is described or depicted, it is intended to encompass that chemical structure as well as tautomers of that structure.
  • enantiomerically pure means a stereomerically pure composition of a compound.
  • a stereochemical ly pure composition is a composition that is free or substantially free of other stereoisomers of that compound.
  • an enantiomerically pure composition of the compound is free or substantially free of the other enantiomer.
  • an enantiomerically pure composition is free or substantially free of the other diastereomers.
  • a compound has an R-configuration at a specific position when it is present in excess compared to the compound having an S-configuration at that position.
  • a compound has an S-configuration at a specific position when it is present in excess compared to the compound having an R- configuration at that position.
  • a disclosed compound can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that disclosed compounds include both solvated and unsolvated forms.
  • a disclosed compound is amorphous or, in another embodiment, a single polymorph.
  • a disclosed compound is a mixture of polymorphs.
  • a disclosed compound is in a crystalline form.
  • Isotopically labeled compounds are also contemplated herein, which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, ,4 C, 1 S N, l8 0, l7 0, 31 P, 32 P, 35 S, l8 F, and 36 C1, respectively.
  • a disclosed compound may have one or more H atom replaced with deuterium.
  • isotopically-labeled disclosed compounds are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon- 14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
  • Isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed in the examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • one or more of the nitrogen atoms of a disclosed compound if present are oxidized to N-oxide.
  • the invention encompasses a method of enhancing (e.g., increasing) CFTR activity in a subject (e.g., a subject suffering from any one or more of the conditions described herein) comprising administering a compound of the invention in an effective amount.
  • the invention also encompasses a method of treating a patient suffering from a condition associated with CFTR activity comprising administering to said patient an effective amount of a compound described herein.
  • the disease is cystic fibrosis.
  • Treating” or “treatment” includes preventing or delaying the onset of the symptoms, complications, or biochemical indicia of a disease, alleviating or ameliorating the symptoms or arresting or inhibiting further development of the disease, condition, or disorder.
  • a "subject” is an animal to be treated or in need of treatment.
  • a “patient” is a human subject in need of treatment.
  • an “effective amount” refers to that amount of an agent that is sufficient to achieve a desired and/or recited effect.
  • an "effective amount" of the therapeutic agent that is sufficient to ameliorate of one or more symptoms of a disorder and/or prevent advancement of a disorder, cause regression of the disorder and/or to achieve a desired effect.
  • modulating encompasses increasing, enhancing, inhibiting, decreasing, suppressing, and the like.
  • increasing and enhancing mean to cause a net gain by either direct or indirect means.
  • inhibiting and decreasing encompass causing a net decrease by either direct or indirect means.
  • CFTR activity is enhanced after administration of a compound described herein when there is an increase in the CFTR activity as compared to that in the absence of the administration of the compound.
  • CFTR activity encompasses, for example, chloride channel activity of the CFTR, and/or other ion transport activity (for example, HCO 3 " transport).
  • the activity of one or more (e.g., one or two) mutant CFTRs is enhanced (e.g., increased).
  • one or more mutant CFTRs e.g., AF508, S549N, G542X, G551 D, Rl 17H, N1303 , W1282X, R553X, 621+lOT, 1717-l OA, 3849+l OkbOT, 2789+50A, 3120+1OA, I507del, R1 162X, 1898+1G>A, 3659delC, G85E, D1 152H, R560T, R347P, 2184insA, A455E, R334W, Q493X, and 2184delA CFTR) is enhanced (e.g., increased).
  • Contemplated patients may have a CFTR mutation(s) from one or more classes, such as without limitation, Class I CFTR mutations, Class II CFTR mutations, Class III CFTR mutations, Class IV CFTR mutations, Class V CFTR mutations, and Class VI mutations.
  • Contemplated subject e.g., human subject
  • CFTR genotypes include, without limitation, homozygote mutations (e.g., AF508 / AF508 and Rl 17H / Rl 17H) and compound heterozygote mutations (e.g., AF508 / G551D; AF508 / A455E;
  • the mutation is a Class I mutation, e.g., a G542X; a Class II/ 1 mutation, e.g., a AF508 / G542X compound heterozygous mutation.
  • a Class I mutation e.g., a G542X
  • a Class II/ 1 mutation e.g., a AF508 / G542X compound heterozygous mutation.
  • the mutation is a Class III mutation, e.g., a G551D; a Class II/ Class III mutation, e.g., a AF508 / G551 D compound heterozygous mutation.
  • the mutation is a Class V mutation, e.g., a A455E; Class II/ Class V mutation, e.g., a AF508 / A455E compound heterozygous mutation.
  • AF508 is the most prevalent mutation of CFTR which results in misfolding of the protein and impaired trafficking from the endoplasmic reticulum to the apical membrane (Dormer et al. (2001). J Cell Sci 1 14, 4073-4081 ; http://www.genet.sickkids.on.ca/app).
  • AF508 CFTR activity is enhanced (e.g., increased).
  • AF508 CFTR activity and/or G542X CFTR activity and/or G551 D CFTR activity and/or A455E CFTR activity is enhanced (e.g., increased).
  • An enhancement of CFTR activity can be measured, for example, using. literature described methods, including for example, Ussing chamber assays, patch clamp assays, and hBE Ieq assay (Devor et al. (2000), Am J Physiol Cell Physiol 279(2): C461-79; Dousmanis et al. (2002), J Gen Physiol 1 19(6): 545-59; Bruscia et al. (2005), PNAS 103(8): 2965-2971 ).
  • a method of treating cystic fibrosis comprising administering a disclosed compound.
  • Disclosed methods can also be used to treat other conditions associated with CFTR activity, including conditions associated with deficient CFTR activity.
  • a method of treating a condition associated with deficient or decreased CFTR activity comprising administering an effective amount of a compound of Formula (IV a) or (Va) or (IV) or (V) that enhances CFTR activity.
  • Non-limiting examples of conditions associated with deficient CFTR activity are cystic fibrosis, congenital bilateral absence of vas deferens (CBAVD), acute, recurrent, or chronic pancreatitis, disseminated bronchiectasis, asthma, allergic pulmonary aspergillosis, smoking-related lung diseases, such as chronic obstructive pulmonary disease (COPD), chronic sinusitis, dry eye disease, protein C deficiency, ⁇ -lipoproteinemia, lysosomal storage disease, type 1 chylomicronemia, mild pulmonary disease, lipid processing deficiencies, type 1 hereditary angioedema, coagulation-fibrinolyis, hereditary hemochromatosis, CFTR-related metabolic syndrome, chronic bronchitis, constipation, pancreatic insufficiency, hereditary emphysema, and Sjogren's syndrome.
  • disclosed methods of treatment further comprise
  • a method of administering a disclosed compound and at least one additional therapeutic agent comprises administering a disclosed compound, and at least two additional therapeutic agents.
  • Additional therapeutic agents include, for example, mucolytic agents, bronchodilators, antibiotics, anti-infective agents, antiinflammatory agents, ion channel modulating agents, therapeutic agents used in gene therapy, CFTR correctors, and CFTR potentiators, or other agents that modulates CFTR activity.
  • at least one additional therapeutic agent is selected from the group consisting of a CFTR corrector and a CFTR potentiator.
  • Non-limiting examples of CFTR correctors and potentiators include VX-770 (I vacaftor), VX-809 (3-(6-( 1 -(2,2- difluorobenzo[d][l ,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, VX-661 (l-(2,2-difluoro- l ,3-benzodioxol-5-yl)-N-[l -[(2R)-2,3-dihydroxypropyl]-6- fluoro-2-(2-hydroxy-l, l -dimethylethyl)-lH-indol-5-yl]- cyclopropanecarboxamide), VX-983, VX-152, VX-440, and Ataluren (PTC124) (3-[5-(2-fluorophenyl)-l ,2,4-oxadia
  • Non-limiting examples of modulators include QBW-251, QR-010, NB-124, and compounds described in, e.g.,
  • Non-limiting examples of anti-inflammatory agents include N6022 (3-(5-(4-(lH- imidazol-l -yl) phenyl)-l -(4-carbamoyl-2-methylphenyl)- 1 H-pyrrol-2-yl) propanoic acid), ⁇ CTX-4430, N1861, N1785, and N91 1 15.
  • the methods described herein can further include
  • the methods described herein can further include administering an additional CFTR modulator or administering at least two additional CFTR modulators.
  • at least one CFTR modulator is a CFTR corrector (e.g., VX-809, VX-661 , VX-983, VX-152, VX-440, GLPG2222 and GLPG2665) or potentiator (e.g., ivacaftor, genistein and GLPG 1837).
  • one of the at least two additional therapeutic agents is a CFTR corrector (e.g., VX-809, VX-661 , VX-983, VX-152, and VX-440) and the other is a CFTR potentiator (e.g., ivacaftor and genistein).
  • one of the at least two additional therapeutic agents is a CFTR corrector (e.g., GLPG2222 or GLPG2665) and the other is a CFTR potentiator (e.g., GLPG 1837).
  • one of the at least two additional therapeutic agents is a CFTR corrector (e.g., VX-809 or VX-661) and the other is a CFTR potentiator (e.g., ivacaftor).
  • at least one CFTR modulator is an agent that enhances read- through of stop codons (e.g., NB 124 or ataluren).
  • this disclosure provides a method of treating a condition associated with deficient or decreased CFTR activity (e.g., cystic fibrosis), which includes administering to a subject in need thereof (e.g., a human patient in need thereof) an effective amount of a disclosed compound and at least one or two additional CFTR therapeutic agent(s) (e.g., at least one or two additional CFTR therapeutic agents, e.g., in which one of the at least one or two additional therapeutic agents is optionally a CFTR corrector or modulator (e.g., VX-809, VX-661, VX-983, VX-152, VX-440, GLPG2222, GLPG2665, NB124, ataluren) and/or the other is a CFTR potentiator (e.g., ivacaftor, genistein, and GLPG 1837); e.g., one of the at least two additional therapeutic agents is GLPG222222
  • the subject's CFTR genotype includes, without limitation, one or more Class I CFTR mutations, one or more Class II CFTR mutations, one or more Class III CFTR mutations, one or more Class IV CFTR mutations, or one or more Class V CFTR mutations, or one or more Class VI CFTR mutations.
  • the subject's CFTR genotype includes, without limitation, one or more homozygote mutations (e.g., AF508 / AF508 or Rl 17H / Rl 17H) and/or one or more compound heterozygote mutations (e.g., AF508 / G551D; AF508 / A455E; AF508 / G542X; A508F / W1204X; R553X / W 1316X; Wl 282X/N 1303K; F508del/Rl 17H; N 1303K/ 3849+1 OkbOT; AF508/R334 W; DF508/G178R, and 591 ⁇ 18 / E831X).
  • one or more homozygote mutations e.g., AF508 / AF508 or Rl 17H / Rl 17H
  • compound heterozygote mutations e.g., AF508 / G551D
  • the subject's CFTR genotype includes a Class I mutation, e.g., a G542X Class 1 mutation, e.g., a AF508 / G542X compound heterozygous mutation.
  • the subject's CFTR genotype includes a Class III mutation, e.g., a G551 D Class III mutation, e.g., a AF508 / G551D compound heterozygous mutation.
  • the subject's CFTR genotype includes a Class V mutation, e.g., a A455E Class V mutation, e.g., a AF508 / A455E compound heterozygous mutation.
  • AF508 CFTR activity and/or G542X CFTR activity and/or G55 ID CFTR activity and/or A455E activity is enhanced (e.g., increased).
  • the enhancement in activity (e.g., increase in activity) provided by the combination of the disclosed compound and one or two additional therapeutic agents is greater than additive when compared to the enhancement in activity provided by each therapeutic component individually.
  • a method of treating a patient having one or more of the following mutations in the CFTR gene comprising administering an effective amount of a disclosed compound.
  • exemplary methods e.g., of a patient having one or more of the following mutations in the CFTR gene: G1244E, G1349D, G178R, G551S, SI 25 IN, S1255P, S549N, S549R , G970R, or R117H, and/or e.g., a patient with one or two copies of the F508del mutation, or one copy of the AF508 mutation and a second mutation that results in a gating effect in the CFTR protein (e.g., a patient that is heterozygous for AF508 and G55 ID mutation), a patient with one copy of the AF508 mutation and a second mutation that results in residual CFTR activity, or a patient with one copy of the AF508 mutation and a second mutation that results in residual CFTR activity, compris
  • a combination therapy e.g., administering (simultaneously or sequentially) an effective amount of ivacaftor to said patient and an effective amount of disclosed compound that may act as an amplifier.
  • Such administration may result, for example, in increased chloride transport in human bronchial epithelial cells with e.g., one or two copies of mutations, e.g, AF508 mutation, as compared to administration of ivacaftor alone.
  • Another combination therapy that includes a disclosed compound may also include an effective amount of a readthrough agent (e.g., ataluren, NB 124) and an effect amount of disclosed compound that may act as an amplifier.
  • a readthrough agent e.g., ataluren, NB 124
  • a beneficial effect of a combination may include, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents.
  • administration of a disclosed compound with ivacaftor alone or with a CFTR corrector agent may result in a level of function (e.g., as measured by chloride activity in HBE cells or patients that have a AF508 mutation, that achieves clinical improvement (or better) as compared to the chloride activity level in cells or patients with a G55 ID mutation receiving ivacaftor alone, or ivacaftor and a corrector agent (lumacaftor or VX-661); or for example, administration of a disclosed compound with ivacaftor alone or ivacaftor with a CFTR corrector agent (e.g., lumacaftor or VX-661) may result in a level of function (e.g., as measured by chloride activity in HBE cells or patients that have a A455E mutation, that achieves clinical improvement (or better) as compared to the chloride activity level at
  • ivacaftor having a G551D class III mutation may show e.g., about two times or more improved activity of ivacaftor as compared to administration of ivacaftor alone.
  • Administration of disclosed therapeutic agents in combination typically is carried out over a defined time period (usually a day, days, weeks, months or years depending upon the combination selected).
  • Combination therapy is intended to embrace administration of multiple therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner.
  • Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single tablet or capsule having a fixed ratio of each therapeutic agent or in multiple, single capsules for each of the therapeutic agents.
  • Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, inhalational routes, intravenous routes, intramuscular routes, and direct absorption through
  • a first therapeutic agent of the combination selected may be administered by intravenous injection or inhalation or nebulizer while the other therapeutic agents of the combination may be administered orally.
  • all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection, inhalation or nebulization.
  • Combination therapy also can embrace the administration of the therapeutic agents as described above in further combination with other biologically active ingredients and non- drug therapies.
  • the combination therapy further comprises a non-drug treatment
  • the non-drug treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and non-drug treatment is achieved.
  • the beneficial effect is still achieved when the non-drug treatment is temporally removed from the administration of the therapeutic agents, perhaps by a day, days or even weeks.
  • the components of a disclosed combination may be administered to a patient simultaneously or sequentially. It will be appreciated that the components may be present in the same pharmaceutically acceptable carrier and, therefore, are administered simultaneously. Alternatively, the active ingredients may be present in separate pharmaceutical carriers, such as, conventional oral dosage forms, that can be administered either simultaneously or sequentially.
  • a method of identifying a candidate agent that increases CFTR activity includes: (i) contacting a cell that expresses a CFTR protein with the candidate agent and a disclosed compound; (ii) measuring the CFTR activity in the cell in the presence of the candidate agent and the disclosed compound; and (iii) comparing the CFTR activity to that in the absence of the test agent, wherein an increase in CFTR activity in the presence of the test agent indicates that the agent increases CFTR activity.
  • the cell expresses a mutant CFTR protein.
  • CFTR activity is measured by measuring chloride channel activity of the CFTR, and/or other ion transport activity.
  • the method is high-throughput.
  • the candidate agent is a CFTR corrector or a CFTR potentiator.
  • pharmaceutically acceptable salt(s) refers to salts of acidic or basic groups that may be present in a disclosed compounds used in disclosed compositions. Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing
  • pharmacologically acceptable anions including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, /?-toluenesulfonate and pamoate (i.e., l, l'-methylene-6 s-(2-hydroxy-3-naphthoate)) salts.
  • Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
  • Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts.
  • Compounds included in the present compositions that include a basic or acidic moiety may also form pharmaceutically acceptable salts with various amino acids.
  • the compounds of the disclosure may contain both acidic and basic groups; for example, one amino and one carboxylic acid group. In such a case, the compound can exist as an acid addition salt, a zwitterion, or a base salt.
  • prodrug refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (such as by esterase, amidase, phosphatase, oxidative and or reductive metabolism) in various locations (such as in the intestinal lumen or upon transit of the intestine, blood or liver). Prodrugs are well known in the art (for example, see Rautio, umpulainen, et al, Nature Reviews Drug Discovery 2008, 7, 255).
  • a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as (Ci -g )alkyl, (C 2 .i 2 )alkylcarbonyloxymethyl, l -(alkylcarbonyloxy)ethyl having from 4 to 9 carbon atoms, 1 -methyl- l-(alkylcarbonyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl-l - (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1
  • a group such as (Ci -g )alkyl, (C 2 .i 2 )alkylcarbonyloxymethyl,
  • a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (Ci-6)aIkylcarbonyloxymethyl, l -((Ci-6)alkylcarbonyloxy)ethyl, 1 -methyl- l -((Ci. 6)alkylcarbonyloxy)ethyl (Ci-6)alkoxycarbonyloxymethyl, N-(Ci.
  • arylalkylcarbonyl and a-aminoalkylcarbonyl or a-aminoalkylcarbonyl-a-aminoalkylcarbonyl, where each a-aminoalkylcarbonyl group is independently selected from the naturally occurring L-amino acids, P(0)(OH) 2 , -P(0)(0(Ci -6 )alkyl) 2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate).
  • a prodrug can be formed, for example, by creation of an amide or carbamate, an N-alkylcarbonyloxyalkyl derivative, an (oxodioxolenyl)methyl derivative, an N-Mannich base, imine or enamine.
  • a secondary amine can be metabolically cleaved to generate a bioactive primary amine, or a tertiary amine can metabolically cleaved to generate a bioactive primary or secondary amine.
  • clathrates of the compounds described herein are also contemplated herein.
  • compositions comprising a pharmaceutically acceptable carrier or excipient and a compound described herein.
  • a disclosed compound, or a pharmaceutically acceptable salt, solvate, clathrate or prodrug therof, can be administered in pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient.
  • the excipient can be chosen based on the expected route of administration of the composition in therapeutic applications.
  • the route of administration of the composition depends on the condition to be treated. For example, intravenous injection may be preferred for treatment of a systemic disorder and oral administration may be preferred to treat a gastrointestinal disorder.
  • the route of administration and the dosage of the composition to be administered can be determined by the skilled artisan without undue experimentation in conjunction with standard dose-response studies. Relevant circumstances to be considered in making those determinations include the condition or conditions to be treated, the choice of composition to be administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms.
  • compositions comprising a disclosed compound or a pharmaceutically acceptable salt, solvate, clathrate or prodrug, can be administered by a variety of routes including, but not limited to, parenteral, oral, pulmonary, ophthalmic, nasal, rectal, vaginal, aural, topical, buccal, transdermal, intravenous, intramuscular, subcutaneous, intradermal, intraocular, intracerebral, intralymphatic, intraarticular, intrathecal and intraperitoneal.
  • the compositions can also include, depending on the formulation desired, pharmaceutical Iy- acceptable, non-toxic carriers or diluents, which are defined as vehicles commonly used to formulate pharmaceutical compositions for animal or human administration.
  • the diluent is selected so as not to affect the biological activity of the pharmacologic agent or composition.
  • examples of such diluents are distilled water, physiological phosphate-buffered saline, Ringer's solutions, dextrose solution, and Hank's solution.
  • the pharmaceutical composition or formulation may also include other carriers, adjuvants, or nontoxic, nontherapeutic, nonimmunogenic stabilizers and the like.
  • Pharmaceutical compositions can also include large, slowly metabolized macromolecules such as proteins, polysaccharides such as chitosan, polylactic acids, polyglycolic acids and copolymers (such as latex functionalized
  • compositions can be administered parenterally such as, for example, by intravenous, intramuscular, intrathecal or subcutaneous injection. Parenteral administration can be accomplished by incorporating a composition into a solution or suspension. Such solutions or suspensions may also include sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents.
  • Parenteral formulations may also include antibacterial agents such as, for example, benzyl alcohol or methyl parabens, antioxidants such as, for example, ascorbic acid or sodium bisulfite and chelating agents such as EDTA. Buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose may also be added.
  • the parenteral preparation can be enclosed in ampules, disposable syringes or multiple dose vials made of glass or plasticAdditionally, auxiliary substances, such as wetting or emulsifying agents, surfactants, pH buffering substances and the like can be present in compositions.
  • Other components of pharmaceutical compositions are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, and mineral oil.
  • glycols such as propylene glycol or polyethylene glycol are preferred liquid carriers, particularly for injectable solutions.
  • Injectable formulations can be prepared either as liquid solutions or suspensions; solid forms suitable for solution in, or suspension in, liquid vehicles prior to injection can also be prepared.
  • the preparation also can also be emulsified or encapsulated in liposomes or micro particles such as polylactide, polyglycolide, or copolymer for enhanced adjuvant effect, as 5 000211
  • compositions and pharmacologic agents described herein can be administered in the form of a depot injection or implant preparation which can be formulated in such a manner as to permit a sustained or pulsatile release of the active ingredient.
  • Additional formulations suitable for other modes of administration include oral, intranasal, and pulmonary formulations, suppositories, transdermal applications and ocular delivery.
  • binders and carriers include, for example, polyalkylene glycols or triglycerides; such suppositories can be formed from mixtures containing the active ingredient in the range of about 0.5% to about 10%, preferably about 1% to about 2%.
  • Oral formulations include excipients, such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, and magnesium carbonate. Topical application can result in transdermal or intradermal delivery.
  • Transdermal delivery can be achieved using a skin patch or using transferosomes.
  • a skin patch or using transferosomes.
  • the pharmaceutical compositions can be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like.
  • Tablets, pills, capsules, troches and the like may also contain binders, excipients, disintegrating agent, lubricants, glidants, sweetening agents, and flavoring agents.
  • binders include microcrystalline cellulose, gum tragacanth or gelatin.
  • excipients include starch or lactose.
  • disintegrating agents include alginic acid, corn starch and the like.
  • lubricants include magnesium stearate or potassium stearate.
  • glidant is colloidal silicon dioxide.
  • sweetening agents include sucrose, saccharin and the like.
  • flavoring agents include peppermint, methyl salicylate, orange flavoring and the like. Materials used in preparing these various compositions should be
  • the composition is administered as a tablet or a capsule.
  • Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both.
  • a syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor, and the like.
  • a pharmaceutical composition may be presented as pessaries, tampons, creams, gels, pastes, foams or spray.
  • the pharmaceutical composition can also be administered by nasal administration.
  • nasally administering or nasal administration includes administering the composition to the mucus membranes of the nasal passage or nasal cavity of the patient.
  • pharmaceutical compositions for nasal administration of a composition include therapeutically effective amounts of the compounds prepared by well-known methods to be administered, for example, as a nasal spray, nasal drop, suspension, gel, ointment, cream or powder. Administration of the composition may also take place using a nasal tampon or nasal sponge.
  • suitable formulations may include biocompatible oil, wax, gel, powder, polymer, or other liquid or solid carriers. Such formulations may be administered by applying directly to affected tissues, for example, a liquid formulation to treat infection of conjunctival tissue can be administered dropwise to the subject's eye, or a cream formulation can be administered to the skin.
  • Rectal administration includes administering the pharmaceutical compositions into the rectum or large intestine. This can be accomplished using suppositories or enemas.
  • Suppository formulations can easily be made by methods known in the art.
  • suppository formulations can be prepared by heating glycerin to about 120 °C, dissolving the pharmaceutical composition in the glycerin, mixing the heated glycerin after which purified water may be added, and pouring the hot mixture into a suppository mold.
  • Transdermal administration includes percutaneous absorption of the composition through the skin.
  • Transdermal formulations include patches, ointments, creams, gels, salves and the like.
  • pulmonary will also mean to include a tissue or cavity that is contingent to the respiratory tract, in particular, the sinuses.
  • an aerosol formulation containing the active agent, a manual pump spray, nebulizer or pressurized metered-dose inhaler as well as dry powder formulations are contemplated.
  • Suitable formulations of this type can also include other agents, such as antistatic agents, to maintain the disclosed compounds as effective aerosols.
  • a drug delivery device for delivering aerosols comprises a suitable aerosol canister with a metering valve containing a pharmaceutical aerosol formulation as described and an actuator housing adapted to hold the canister and allow for drug delivery.
  • the canister in the drug delivery device has a head space representing greater than about 15% of the total volume of the canister.
  • the compound intended for pulmonary administration is dissolved, suspended or emulsified in a mixture of a solvent, surfactant and propellant. The mixture is maintained under pressure in a canister that has been sealed with a metering valve.
  • the disclosure also encompasses the treatment of a condition associated with a dysfunction in proteostasis in a subject comprising administering to said subject an effective amount of a disclosed compound that enhances, improves or restores proteostasis of a protein.
  • Proteostasis refers to protein homeostasis. Dysfunction in protein homeostasis is a result of protein misfolding, protein aggregation, defective protein trafficking or protein degradation.
  • the disclosure contemplates administering a disclosed compound e.g., Formula (IVa), (Va), (IV), or (V) that corrects protein misfolding, reduces protein aggregation, corrects or restores protein trafficking and/or affects protein degradation for the treatment of a condition associated with a dysfunction in proteostasis.
  • a disclosed compound e.g., Formula (IVa), (Va), (IV), or (V) that corrects protein misfolding and/or corrects or restores protein trafficking is administered.
  • the mutated or defective enzyme is the cystic fibrosis transmembrane conductance regulator (CFTR).
  • AF508 is a deletion ( ⁇ ) of three nucleotides resulting in a loss of the amino acid phenylalanine (F) at the 508th (508) position on the protein.
  • F amino acid phenylalanine
  • mutated cystic fibrosis transmembrane conductance regulator exists in a misfolded state and is characterized by altered trafficking as compared to the wild type CFTR.
  • Additional exemplary proteins of which there can be a dysfunction in proteostasis, for example that can exist in a misfolded state include, but are not limited to, glucocerebrosidase, hexosamine A, aspartylglucsaminidase, a-galactosidase A, cysteine transporter, acid ceremidase, acid oc-L-fucosidase, protective protein, cathepsin A, acid ⁇ -glucosidase, acid ⁇ - galactosidase, iduronate 2-sulfatase, a-L-iduronidase, galactocerebrosidase, acid a - mannosidase, acid ⁇ -mannosidase, arylsulfat
  • Protein conformational diseases encompass gain of function disorders and loss of function disorders.
  • the protein conformational disease is a gain of function disorder.
  • gain of function disorder is a disease characterized by increased aggregation-associated
  • Gain of function diseases include, but are not limited to, neurodegenerative diseases associated with aggregation of polyglutamine, Lewy body diseases, amyotrophic lateral sclerosis, transthyretin-associated aggregation diseases, Alzheimer's disease, Machado-Joseph disease, cerebral B-amyloid angiopathy, retinal ganglion cell degeneration, tauopathies (progressive supranuclear palsy, corticobasal degeneration, frontotemporal lobar degeneration), cerebral hemorrhage with amyloidosis, Alexander disease, Serpinopathies, familial amyloidotic neuropathy, senile systemic amyloidosis, ApoAI amyloidosis, ApoAII amyloidosis, ApoAIV amyloidosis, familial amyloidosis of the Finnish type, lysozyme amyloidosis,
  • spinocerebellar ataxia 1, Angelman syndrome, giant axon neuropathy, inclusion body myopathy with Paget disease of bone, frontotemporal dementia (IBMPFD) and prion diseases.
  • Neurodegenerative diseases associated with aggregation of polyglutamine include, but are not limited to, Huntington's disease, dentatorubral and pallidoluysian atrophy, several forms of spino-cerebellar ataxia, and spinal and bulbar muscular atrophy.
  • Alzheimer's disease is characterized by the formation of two types of aggregates: extracellular aggregates of ⁇ peptide and intracellular aggregates of the microtubule associated protein tau.
  • Transthyretin- associated aggregation diseases include, for example, senile systemic amyloidoses and familial amyloidotic neuropathy.
  • Lewy body diseases are characterized by an aggregation of a- synuclein protein and include, for example, Parkinson's disease, Lewy body dementia (LBD) and multiple system atrophy (SMA).
  • Prion diseases also known as transmissible spongiform encephalopathies or TSEs are characterized by aggregation of prion proteins.
  • Exemplary human prion diseases are Creutzfeldt-Jakob Disease (CJD), Variant Creutzfeldt-Jakob Disease, Gerstmann-Straussler-Scheinker Syndrome, Fatal Familial Insomnia and Kuru.
  • CJD Creutzfeldt-Jakob Disease
  • Variant Creutzfeldt-Jakob Disease Gerstmann-Straussler-Scheinker Syndrome
  • Fatal Familial Insomnia and Kuru.
  • the misfolded protein is alpha-1 anti-trypsin.
  • the protein conformation disease is a loss of function disorder.
  • the terms "loss of function disease” and “loss of function disorder” are used interchangeably herein.
  • Loss of function diseases are a group of diseases characterized by inefficient folding of a protein resulting in excessive degradation of the protein.
  • Loss of function diseases include, for example, lysosomal storage diseases. Lysosomal storage diseases are a group of diseases characterized by a specific lysosomal enzyme deficiency which may occur in a variety of tissues, resulting in the build-up of molecules normally degraded by the deficient enzyme.
  • Lysosomal enzyme deficiency can be in a lysosomal hydrolase or a protein involved in the lysosomal trafficking.
  • Lysosomal storage diseases include, but are not limited to, aspartylglucosaminuria, Fabry's disease, Batten disease, Cystinosis, Farber, Fucosidosis, Galactasidosialidosis, Gaucher's disease (including Types 1, 2 and 3), Gm l gangliosidosis, Hunter's disease, Hurler-Scheie's disease, Krabbe's disease, oc-Mannosidosis, ⁇ -Mannosidosis, Maroteaux-Lamy's disease, Metachromatic Leukodystrophy, Morquio A syndrome, Morquio B syndrome, Mucolipidosis II, Mucolipidosis III, Neimann-Pick Disease (including Types A, B and C), Pompe's disease, Sandhoff disease, Sanfilippo syndrome (including Types A, B, C and
  • the disease associated with a dysfunction in proteostasis is a cardiovascular disease.
  • Cardiovascular diseases include, but are not limited to, coronary artery disease, myocardial infarction, stroke, restenosis and arteriosclerosis.
  • Conditions associated with a dysfunction of proteostasis also include ischemic conditions, such as,
  • ischemia/reperfusion injury myocardial ischemia, stable angina, unstable angina, stroke, ischemic heart disease and cerebral ischemia.
  • the disease associated with a dysfunction in proteostasis is diabetes and/or complications of diabetes, including, but not limited to, diabetic retinopathy, cardiomyopathy, neuropathy, nephropathy, and impaired wound healing.
  • the disease associated with a dysfunction in proteostasis is an ocular disease including, but not limited to, age-related macular degeneration (AMD), diabetic macular edema (DME), diabetic retinopathy, glaucoma, cataracts, retinitis pigmentosa (RP) and dry macular degeneration.
  • AMD age-related macular degeneration
  • DME diabetic macular edema
  • RP retinitis pigmentosa
  • dry macular degeneration including, but not limited to, age-related macular degeneration (AMD), diabetic macular edema (DME), diabetic retinopathy, glaucoma, cataracts, retinitis pigmentosa (RP) and dry macular degeneration.
  • a disclosed method is directed to treating a disease associated with a dysfunction in proteostasis, wherein the disease affects the respiratory system or the pancreas.
  • a contemplated method encompass treating a condition selected from the group consisting of polyendocrinopathy hyperinsulinemia, diabetes mellitus, Charcot-Marie Tooth syndrome, Pelizaeus-Merzbacher disease, and
  • hemoglobinopathies such as sickle cell anemia
  • an inflammatory disease such as asthma
  • inflammatory bowel disease such as colitis, ankylosing spondylitis
  • intermediate filament diseases such as non-alcoholic and alcoholic fatty liver disease
  • drug induced lung damage such as methotrexate-induced lung damage
  • Additional contemplated conditions include those associated with a defect in protein trafficking and that can be treated according to disclosed methods include: PGP mutations, hERG trafficking mutations, nephrongenic diabetes insipidus mutations in the arginine- vasopressin receptor 2, persistent hyperinsulinemic hypoglycemia of infancy (PHHl) mutations in the sulfonylurea receptor 1, and a lAT.
  • Ussing measurements are used to measure CFTR activity.
  • primary lung epithelial cells hBEs
  • hBEs primary lung epithelial cells homozygous for the Cystic Fibrosis-causing AF508 mutation are differentiated for a minimum of 4 weeks in an air-liquid interface on Snap Well filter plates prior to the Ussing measurements.
  • Cells are apically mucus-washed for 30 minutes prior to treatment with compounds.
  • the basolateral media is removed and replaced with media containing the compound of interest diluted to its final concentration from DMSO stocks.
  • Treated cells are incubated at 37 °C and 5% C0 2 for 24 hours.
  • the cells on filters are transferred to the Ussing chamber and equilibrated for 30 minutes.
  • the inhibitable current (that current that is blocked by CFTRinh-172) is measured as the specific activity of the AF508-CFTR channel, and increases in response to compound in this activity over that observed in vehicle-treated samples are identified as the correction of AF508-CFTR function imparted by the compound tested.
  • the plates containing the cells were then placed in pre-warmed heating blocks at 36 °C ⁇ 0.5 for 15 minutes before measurements are taken.
  • the transepithelial voltage (VT) and conductance (GT) were measured using a custom 24 channel current clamp (TECC- 24) with 24 well electrode manifold.
  • the Ieq assay measurements were made following additions with standardized time periods:
  • the baseline VT and G values were measured for approximately 20 minutes.
  • the activity data captured was the area under the curve (AUC) for the traces of the equivalent chloride current.
  • the AUC was collected from the time of the forskolin/VX-770 addition until the inhibition by bumetanide addition. Correction in response to compound treatment was scored as the increase in the AUC for compound-treated samples over that of vehicle-treated samples.
  • the results are shown below in Table 2.
  • the results are shown below in Table 2. (** indicates activity >200% of VX-809 (1 uM) with compound at 10 uM and VX- 809 at 1 uM; * indicates activity 100-200% of VX-809 (1 uM) with compound at 10 uM and VX-809 at 1 uM.
  • m indicates activity >200% of VX-809 (3 uM) with compound at 10 uM and VX-809 at 3 uM; * indicates acti vity 100-200% of VX-809 (3 uM) with compound at 10 uM and VX-809 at 3 uM.
  • Ussing measurements can be used to measure CFTR activity.
  • primary lung epithelial cells hBEs
  • hBEs primary lung epithelial cells
  • Cells are apically mucus-washed for 30 minutes prior to treatment with compounds.
  • the basolateral media is removed and replaced with media containing the compound of interest diluted to its final concentration from DMSO or aqueous stocks.
  • Treated cells are incubated at 37 °C and 5% C0 2 for 24 hours. At the end of the treatment period, the cells on filters are transferred to the Ussing chamber and equilibrated for 30 minutes.
  • the forskolin-sensitive current and inhibitable current are measured as the specific activity of the AF508-CFTR channel, and increase in response to compound in this activity over that observed in vehicle-treated samples are identified as the correction of AF508-CFTR function imparted by the compound tested.
  • Ussing measurements can be used to measure CFTR activity.
  • primary lung epithelial cells hBEs
  • Cystic Fibrosis-causing class III mutation are differentiated for a minimum of 4 weeks in an air-liquid interface on Snap WellTM filter plates prior to the Ussing measurements.
  • Cells are apically mucus-washed for 30 minutes prior to treatment with compounds.
  • the basolateral media is removed and replaced with media containing the compound of interest diluted to its final concentration from DMSO stocks.
  • Treated cells are incubated at 37 °C and 5% C0 2 for 24 hours. At the end of the treatment period, the cells on filters are transferred to the Ussing chamber and equilibrated for 30 minutes.
  • VX-770 or Genistein to the apical chamber to potentiate AF508-CFTR channel opening.
  • hBEs primary lung epithelial cells
  • Cystic Fibrosis-causing class V mutation are differentiated for a minimum of 4 weeks in an air-liquid interface on hBEs
  • the forskolin-sensitive current and inhibitable current are measured as the specific activity of the AF508-CFTR channel, and increases in response to compound in this activity over that observed in vehicle-treated samples are identified as the correction of AF508-CFTR function imparted by the compound tested.
  • V T transepithelial voltage
  • GT conductance
  • V T and GT values are measured for approximately 20 minutes.
  • Benzamil is added to block ENaC for 15 minutes.
  • the activity data captured is the area under the curve (AUC) for the traces of the equivalent chloride current.
  • the AUC is collected from the time of the forskoIin/VX-770 addition until the inhibition by bumetanide addition. Correction in response to compound treatment is scored as the increase in the AUC for compound-treated samples over that of vehicle-treated samples.

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Abstract

The present disclosure is based, in part, on the discovery that disclosed compounds such as those having Formula (IVa), (Va), (IV), or (V) can increase cystic fibrosis transmembrane conductance regulator (CFTR) activity as measured in human bronchial epithelial (hBE) cells.

Description

DERIVATIVES OF 5-(HETERO)ARYLPYRAZOL-3-CARBOXYLIC AMIDE OR 1 -(HETERO)ARYLTRIAZOL-4-CARBOXYLIC AMIDE USEFUL FOR THE TREATMENT OF INTER ALIA CYSTIC FIBROSIS
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of, and priority to, U.S. provisional application serial numbers 62/102,227, filed January 12, 2015, and 62/096,384, filed December 23, 2014, the contents of each of which is hereby incorporated by reference herein in its entirety.
BACKGROUND
[0002] Cells normally maintain a balance between protein synthesis, folding, trafficking, aggregation, and degradation, referred to as protein homeostasis, utilizing sensors and networks ofpathways (Sitia et al., Nature 426: 891 -894, 2003; Ron et &\., Nat Rev Mol Cell Biol 8: 519- 529, 2007). The cellular maintenance of protein homeostasis, or proteostasis, refers to controlling the conformation, binding interactions, location and concentration of individual proteins making up the proteome. Protein folding in vivo is accomplished through interactions between the folding polypeptide chain and macromolecular cellular components, including multiple classes of chaperones and folding enzymes, which minimize aggregation (Wiseman et al., Cell 131: 809-821 , 2007). Whether a given protein folds in a certain cell type depends on the distribution, concentration, and subcellular localization of chaperones, folding enzymes, metabolites and the like (Wiseman et al.). Cystic fibrosis and other maladies of protein misfolding arise as a result of an imbalance in the capacity of the protein homeostasis
(proteostasis) environment to handle the reduced energetic stability of misfolded, mutated proteins that are critical for normal physiology (Balch et al., Science 319, 916-9 (2008);
Powers, et al., Annu Rev Biochem 78, 959-91 (2009); Hurt et al., FEBS Lett 583, 2639-46 (2009)). [0003] Cystic Fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene which encodes a multi-membrane spanning epithelial chloride channel (Riordan et al., Annu Rev Biochem 11, 701-26 (2008)). Approximately ninety percent of patients have a deletion of phenylalanine (Phe) 508 (AF508) on at least one allele. This mutation results in disruption of the energetics of the protein fold leading to degradation of CFTR in the endoplasmic reticulum (ER). The AF508 mutation is thus associated with defective folding and trafficking, as well as enhanced degradation of the mutant CFTR protein (Qu et al., J Biol Chem 272, 15739-44 (1997)). The loss of a functional CFTR channel at the plasma membrane disrupts ionic homeostasis (CF, Na+, HCO3 ") and airway surface hydration leading to reduced lung function (Riordan et al.). Reduced periciliary liquid volume and increased mucus viscosity impede mucociliary clearance resulting in chronic infection and inflammation, phenotypic hallmarks of CF disease (Boucher, J Intern Med 26\ , 5-16 (2007)). In addition to respiratory dysfunction, AF508 CFTR also impacts the normal function of additional organs (pancreas, intestine, gall bladder), suggesting that the loss-of-function impacts multiple downstream pathways that will require correction.
[0004] In addition to cystic fibrosis, mutations in the CFTR gene and/or the activity of the CFTR channel has also been implicated in other conditions, including for example, congenital bilateral absence of vas deferens (CBAVD), acute, recurrent, or chronic pancreatitis, disseminated bronchiectasis, asthma, allergic pulmonary aspergillosis, smoking-related lung diseases, such as chronic obstructive pulmonary disease (COPD), dry eye disease, Sjogren's syndrome and chronic sinusitis, (Sloane et al. (2012), PLoS ONE 7(6):
e39809.doi: 10.1371/journal. pone.0039809; Bombieri et al. (201 1), J Cyst Fibros. 201 1 Jun; 10 Suppl 2:S86-102; (Albert et al. (2008). Clinical Respiratory Medicine, Third Ed., Mosby Inc.; Levin et al. (2005), Invest Ophthalmol Vis Sci., 46(4): 1428-34; Froussard (2007), Pancreas 35(1 ): 94-5).
[0005] There remains a need in the art for compounds, compositions and methods of increasing CFTR activity as well as for methods of treating CF, other CFTR-related diseases, and other maladies of protein misfolding. SUMMARY
[0006] The present disclosure is based, in part, on the discovery that disclosed compounds can increase cystic fibrosis transmembrane conductance regulator (CFTR) activity as measured in human bronchial epithelial (hBE) cells. [0007] For example, provided herein, in an embodiment, are compounds having the Formula (IV) or (V):
Figure imgf000004_0001
Figure imgf000004_0002
and pharmaceutically acceptable salts, stereoisomers, and prodrugs thereof, wherein:
Xi is CH or N; wherein when Xi is N, Rz is not present and the nitrogen with Rz has a double bond with the adjacent N and there is a single bond between Xi and the adjacent N, and when Xi is CH, Xi has a double bond with the nitrogen adjacent, and Rz is selected from the group consisting of H, and Ci-3alkyl, and the nitrogen with Rz has a single bond with the adjacent N;
X3 is selected from the group consisting of O, S, and NRht,;
pp is 1, 2, or 3; Ri i is independently selected for each occurrence from the group consisting of hydrogen, halogen, C^alkyl (optionally substituted by one, two or three halogens);
Li is selected from the group consisting of Ci-6 alkylene, C3.6 cycloalkylene, C3- 6cycloalkylene-Ci.4 alkylene, Ci-3alkylene-NRhh-S(0)w-i - Ci-3 alkylene-S(0)w-NRhh-, C3.
6cycloalkylene-Co-2 alkylene-S(0)w-NRhh, and C3-6 cycloalkylene- Co-2alkylene NRhh-S(0)w-j wherein Li may be optionally substituted by one, two or three substituents selected from the group consisting of halogen, hydroxyl, C] -3alkyl (optionally substituted by one, two or three substituents each selected independently from Rfr);
R44 is selected from the group consisting of H, halogen, hydroxyl, Ci-3alkoxy, heterocycle, and a 5-6 membered monocyclic or 8-10 membered bicyclic heteroaryl having one, two or three heteroatoms each selected from O, N, and S; wherein the heterocycle and the heteroaryl may be optionally substituted by one or two substituents each selected independently from Rgg;
Rfr is selected for each occurrence from group consisting of halogen, hydroxyl, Ci- 4alkyl, C,-4alkyoxy, C2.4alkenyl, C3-6cycloalkyl, -NR'R", -NR'-S(0)w-Ci-3alkyl, S(0)w-
NR'R", and -S(0)w-Ci-3alkyl, where w is 0, 1, or 2, wherein Ci-4alkyl, C)-4alkyoxy, C2-4alkenyl and C3.6cycloalkyl may be optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, -NR'R", -NR'-S(0)w- C,-3alkyl, S(0)w-NR'R", and -SiO d^alkyl;
Rgg is selected for each occurrence from group consisting of halogen, hydroxyl, C\.
6alkyl, d-6alkyoxy, C2-6alkenyl, C3-6cycloalkyl, -NR'R", -NR'-S(0)w-Ci-3alkyl, S(0)w- NR'R", and -S(0)w-C|.3alkyl, where w is 0, 1 , or 2, wherein
Figure imgf000005_0001
C2-6alkenyl and C3-6cycloalkyl may each be optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen,
Figure imgf000005_0002
Ci-6alkoxy, hydroxyl, C(0)OH, -C(0)OC)-6alkyl, -0-C3-6cycloalkyl, -O-heterocycle, -O-heteroaryl, -O-phenyl, - NR'R", -NR'-S(0)w-C,.3alkyl, S(0)w-NR'R", and -S(0)w-C,.3alkyl;
w is 0, 1 or 2; and
Rhh is selected for each occurrence from the group consisting of H, Ci.6alkyl and C3- 6cycloalkyl. [0008] Also contemplated herein are pharmaceutical compositions that include a disclosed compound such as those compounds having Formula (IVa), (Va), (IV), or (V) and a pharmaceutically acceptable carrier or excipient. In certain embodiments, the compositions can include at least one additional CFTR modulator as described anywhere herein or at least two additional CFTR modulators, each independently as described anywhere herein.
[0009] In additional embodiments, a method of enhancing (e.g., increasing) cystic fibrosis transmembrane conductance regulator (CFTR) activity in a subject in need thereof is provided comprising administering to said subject an effective amount of a compound of Formula (IVa), (Va), (IV), or (V). [0010] In certain of these embodiments, the activity of one or more (e.g., one or two) mutant CFTRs (e.g., AF508, S549N, G542X, G551D, Rl 17H, N1303K, W1282X, R553X, 621+1 G>T, 1717-1G>A, 3849+l OkbOT, 2789+5G>A, 3120+1OA, I507del, R1 162X, 1898+1 G>A, 3659delC, G85E, Dl 152H, R560T, R347P, 2184insA, A455E, R334W, Q493X, and 2184delA CFTR) is enhanced (e.g., increased). In certain embodiments, AF508 CFTR activity is enhanced (e.g., increased). In other embodiments, the activities of two mutant CFTRs (e.g., AF508 and G551D; AF508 and A455E; or G542X; A508F) are enhanced (e.g., increased).
[0011] In certain of these embodiments, the subject (e.g., a human patient) is suffering from a disease associated with decreased CFTR activity (e.g., cystic fibrosis, congenital bilateral absence of vas deferens (CBAVD), acute, recurrent, or chronic pancreatitis, disseminated bronchiectasis, asthma, allergic pulmonary aspergillosis, chronic obstructive pulmonary disease (COPD), chronic sinusitis, dry eye disease, protein C deficiency, Α-β-lipoproteinemia, lysosomal storage disease, type 1 chylomicronemia, mild pulmonary disease, lipid processing deficiencies, type 1 hereditary angioedema, coagulation-fibrinolyis, hereditary
hemochromatosis, CFTR-related metabolic syndrome, chronic bronchitis, constipation, pancreatic insufficiency, hereditary emphysema, Sjogren's syndrome, familial
hypercholesterolemia, I-cell disease/pseudo-Hurler, mucopolysaccharidoses, Sandhof/Tay- Sachs, Crigler-Najjar type II, polyendocrinopathy/hyperinsulemia, Diabetes mellitus, Laron dwarfism, myleoperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1 , congenital hyperthyroidism, osteogenesis imperfecta, hereditary
hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI), neurophyseal DI, nephrogenic DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, Huntington's disease, spinocerebellar ataxia type I, spinal and bulbar muscular atrophy, dentatorubral pallidoluysian, myotonic dystrophy, hereditary Creutzfeldt- Jakob disease (due to prion protein processing defect), Fabry disease, and Straussler-Scheinker syndrome). In certain embodiments, the disease is cystic fibrosis. [0012] In yet additional aspects, the disclosure is directed to treating a patient suffering from cystic fibrosis comprising administering to said patient an effective amount of a disclosed compound.
[0013] In some embodiments, the methods described herein can further include
administering an additional CFTR modulator or administering at least two additional CFTR modulators. In certain embodiments, at least one CFTR modulator is a CFTR corrector (e.g., VX-809, VX-661 , VX-983, VX-152, VX-440, GLPG2222 and GLPG2665) or potentiator (e.g., ivacaftor and genistein). In certain of these embodiments, one of the at least two additional therapeutic agents is a CFTR corrector (e.g., VX-809, VX-661 , VX-983, VX-152, VX-440, GLPG2222 and GLPG2665) and the other is a CFTR potentiator (e.g., ivacaftor and genistein). [0014] In a further aspect, a method of identifying a candidate agent that increases CFTR activity is provided, which includes: (i) contacting a cell that expresses a CFTR protein with the candidate agent and a disclosed compound; (ii) measuring the CFTR activity in the cell in the presence of the candidate agent and the disclosed compound; and (iii) comparing the CFTR activity to that in the absence of the test agent, wherein an increase in CFTR activity in the presence of the test agent indicates that the agent increases CFTR activity. In certain embodiments, the cell expresses a mutant CFTR protein. In certain embodiments, CFTR activity is measured by measuring chloride channel activity of the CFTR, and/or other ion transport activity. In certain of these embodiments, the method is high-throughput. In certain of these embodiments, the candidate agent is a CFTR corrector or a CFTR potentiator.
DETAILED DESCRIPTION
[0015] As used herein, the words "a" and "an" are meant to include one or more unless otherwise specified. For example, the term "an agent" encompasses both a single agent and a combination of two or more agents.
[0016] As discussed above, the present disclosure is directed in part to compounds as described herein having the Formula (IV) or (V), or a pharmaceutically acceptable salt, prodrug or solvate thereof, pharmaceutical compositions, methods of increasing CFTR activity and methods of treating cystic fibrosis.
[0017] For example, disclosed herein, in an embodiment, are compounds having the Formula (IV) or (V):
Figure imgf000008_0001
and pharmaceutically acceptable salts, stereoisomers, and prodrugs thereof, wherein: Xi is CH or N; wherein when Xi is N, Rz is not present and the nitrogen with Rz has a double bond with the adjacent N and there is a single bond between Xi and the adjacent N, and when Xi is CH, Xi has a double bond with the nitrogen adjacent, and Rz is selected from the group consisting of H, and Ci-3alkyl, and the nitrogen with Rz has a single bond with the adjacent N;
X3 is selected from the group consisting of O, S, and NRhh;
pp is 1 , 2, or 3;
Ri 1 is independently selected for each occurrence from the group consisting of hydrogen, halogen, Ci-4alkyl (optionally substituted by one, two or three halogens);
Li is selected from the group consisting of Ci.6 alkylene, C3.6 cycloalkylene, C3-
Figure imgf000009_0001
alkylene, Ci-3alkylene-NRhh-S(0)w-j - Ci-3 alkylene-S(0)w-NRhh-, C3- 6cycloalkylene-Co-2 alkylene-S(0)w-NRhh, and C3-6 cycloalkylene- Co-2alkylene NRhh-S(0)w-; wherein Li may be optionally substituted by one, two or three substituents selected from the group consisting of halogen, hydroxyl, Ci-3alkyl (optionally substituted by one, two or three substituents each selected independently from Rfj);
R44 is selected from the group consisting of H, halogen, hydroxyl,
Figure imgf000009_0002
heterocycle, and a 5-6 membered monocyclic or 8-10 membered bicyclic heteroaryl having one, two or three heteroatoms each selected from O, N, and S; wherein the heterocycle and the heteroaryl may be optionally substituted by one or two substituents each selected independently from Rgg;
Rfr is selected for each occurrence from group consisting of halogen, hydroxyl, C\. 4alkyl, C alkyoxy, C2.4alkenyl, C3-6cycloalkyl, -NR'R", -NR'-S(0)w-Ci-3alkyl, S(0)w- NR'R", and -S(0)w-Ci-3alkyl, where w is 0, 1 , or 2, wherein Ci-4alkyl, Ci-4alkyoxy, C2-4alkenyl and C3-6cycloalkyl may be optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, -NR'R", -NR'-S(0)w- C1-3alkyl, S(0)w-NR'R", and -S(0)w-Ci-3alkyl;
Rgg is selected for each occurrence from group consisting of halogen, hydroxyl, Ci. ealkyl, C1-6alkyoxy, C2-6alkenyl, C3-6cycloalkyl, -NR'R", -NR'-S(0)w-Ci-3alkyl, S(0)w- NR'R", and -S(0)w-Ci.3alkyl, where w is 0, 1 , or 2, wherein Ci-6alkyl, d-6alkyoxy, C2-6alkenyl and C3-6cycloalkyl may each be optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, Ci-ealkyl, Ci-ealkoxy, hydroxyl, C(0)OH, -C(0)OCi-6alkyl, -0-C3-6cycloalkyl, -O-heterocycle, -O-heteroaryl, -O-phenyl, - NR'R", -NR'-S(0)w-Ci-3alkyl, S(0)w-NR'R", and -S(0)w-C,.3alkyl;
w is 0, 1 or 2; and
Rhh is selected for each occurrence from the group consisting of H, Ci-6alkyl and C3. 6cycloalkyl.
[0018] In certain embodiments, Li may be Ci-3alkylene or C3-5cycloalkylene and/or Xi is CH or C.
[0019] Also provided herein are compounds having a formula selected from
Figure imgf000010_0001
wherein qq is 0 or 1 ( and R44, Ri 1 are defined above).
[0020] For example, provided herein are compounds having formula:
Figure imgf000011_0001
[0021] In certain embodiments, R44 of one or more of above formulas is selected from the group consisting of: pyrrolidinyl, piperidinyl, tetrahydropyranyl, and tetrahydrofuranyl. In other embodiments, R44 is selected from the group consisting of:
Figure imgf000011_0002
wherein X independently for each occurrence is selected from the group consisting of O, S, NRhh, C, C(Rsg), and C(Rg8)(R99); X2 independently for each occurrence is selected from the group consisting of O, S and NRhh; R" is H or C]-4alkyl, each R66, R77, ss and R99 is independently selected for each occurrence from H and Rgg, and n is 0, 1, 2, or 3.
[0022] In certain embodiments, each R66, R77, ss and R99 is independently selected for each occurrence from the group consisting of hydrogen, halogen, hydroxyl, Ci-6 alkyl, C3-6 cycloalkyl, and heterocycle, wherein Ci-6 alkyl, C3-6 cycloalkyl, and heterocycle are optionally substituted by one, two or three substituents each independently selected from the group consisting of hydroxyl, Ci-6 alkyl, Ci^ alkoxy (optionally substituted by C3-6cycloalkyl, heterocycle, -Ci_2alkyl-heterocycle and Ci-2alkyl- C3-6cycloalkyl), -S(0)w-Ci-3 alkyl (w is 0, 1 , or 2) and -NR'S(0)2Ci-6 alkyl; and R' is independently selected for each occurrence from H and Ci-4 alkyl and/or pp is 0, 1 or 2, and Ri 1 is selected from H, F, or methyl.
[0023] Also disclosed herein are compounds such as those having the Formula (IVa) or
(Va):
Figure imgf000012_0001
(IVa);
Figure imgf000012_0002
(Va); or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein:
Ri is selected from the group consisting of:
Figure imgf000013_0001
R2 is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl;
R3a is selected from the group consisting of hydrogen, optionally substituted CpCio alkyl, optionally substituted C2-Ci0 alkenyl, optionally substituted C2-Cio alkynyl, optionally substituted C3-Ci2 cycloalkyl, optionally substituted C3-Ci2 cycloalkenyl, optionally substituted aryl, halo, ORc, NRd j, C(0)ORc, N02, CN, C(0)Rc, C(0)C(0)Rc, C(0)NRdRd, NRdC(0)Rc, NRdS(0)nRc, N(Rd)(COORc), NRdC(0)C(0)Rc, NRdC(0)NRdRd, NRdS(0)„NR«|Rd,
NRdS(0)nRc, S(0)nRc, S(0)nNRdRd, OCCO Rc, (C=NRd)Rc, optionally substituted heterocyclic and optionally substituted heteroaryl;
R4a is selected from the group consisting of hydrogen, optionally substituted Ci-Cio alkyl, optionally substituted C2-Cio alkenyl, optionally substituted C2-Ci0 alkynyl, optionally substituted C3-Ci2 cycloalkyl, optionally substituted C3-Ci2 cycloalkenyl, optionally substituted aryl, halo, ORc, S(0)nRc, NR^ d, C(0)ORc, N02, CN, C(0)Rc, C(0)C(0)Rc, C(0)NR<jRd, NRdC(0)Rc, NRdS(0)Rc, N(Rd)(COORc), NRdC(0)C(0)Rc, Ν¾0(0)Ν¾¾, NRdS(0)nRdRd, NRdS(0)nRc, S(0)NRdRd, OC(0)ORc, (C=NRd)Rc, optionally substituted heterocyclic and optionally substituted heteroaryl;
R4b is selected from the group consisting of hydrogen, optionally substituted Ci-Ci0 alkyl, optionally substituted C2-Cio alkenyl, optionally substituted C2-Cio alkynyl, optionally substituted C3-Ci2 cycloalkyl, optionally substituted C3-C]2 cycloalkenyl, optionally substituted aryl, optionally substituted heterocyclic and optionally substituted heteroaryl;
Ra is selected from the group consisting of hydrogen, optionally substituted CpCio alkyl, optionally substituted C2-Ci0 alkenyl, optionally substituted C2-Ci0 alkynyl, optionally substituted CrCi2 cycloalkyl, optionally substituted C3-Ci2 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, C(0)ORc, C(0)Rc, C(0)C(0)Rc and S(0)nRc;
or alternatively, Ra and the nitrogen atom to which it is attached is taken together with an adjacent C(Rbi)(Rbi) or C(Rb2)(Rb2) to form an optionally substituted, 4- to 12-membered heterocyclic ring containing one or more ring nitrogen atoms, wherein said heterocyclic ring optionally contains one or more ring heteroatoms selected from oxygen and sulfur;
each Rbi and R½ is independently selected from the group consisting of hydrogen, optionally substituted CpCio alkyl, optionally substituted C2-Cio alkenyl, optionally substituted C2-Cio alkynyl, optionally substituted C3-Ci2 cycloalkyl, optionally substituted C3-Ci2 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, ORc, NRjRd, C(0)ORc, N02, CN, C(0)Rc, C(0)C(0)Rc,
C(0)NRdRd, NRdC(0)Rc, NRdS(0)nRc, N(Rd)(COORc), NRdC(0)C(0)Rc, NRdC(0)NRdRd, NRdS(0)nNRdRd, NRdS(0)nRc, S(0)nRc, S(0)nNRdR<i, OC(0)ORc and (C=NRd)Rc; or alternatively, two geminal Rbi groups or two geminal Rb2 groups and the carbon to which they are attached are taken together to form a C(O) group, or yet alternatively, two geminal Rbi groups or two geminal Rb2 groups are taken together with the carbon atom to which they are attached to form a spiro C3-Ci2 cycloalkyl, a spiro C3-Ci2 cycloalkenyl, a spiro heterocyclic, a spiro aryl or spiro heteroaryl, each optionally substituted;
Y is selected from the group consisting of S(0)n>, Ν¾, NRdS(0)n, NRdS(0)nNRd, NRdC(O), NRdC(0)0, NR<,C(0)C(0), NRdC(0)NRd, S(0)nNR<,, and O;
each Rc is independently selected from the group consisting of hydrogen, optionally substituted CpCio alkyl, optionally substituted C2-Ci0 alkenyl, optionally substituted C2-Cio alkynyl, optionally substituted C3-Ci2 cycloalkyl, optionally substituted C3-Ci2 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;
each Rd is independently selected from the group consisting of hydrogen, optionally substituted Ci-Cio alkyl, optionally substituted C2-Cio alkenyl, optionally substituted C2-Cio alkynyl, optionally substituted Ci-Cio alkoxy, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-Ci2 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl; or two geminal Ra groups are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic or an optionally substituted heteroaryl;
k is 0 or 1 ;
m is 0, 1 , 2, 3, 4, or 5;
each n is independently 0, 1 or 2.
[0024] In some embodiments, m is 0, 1 or 2 (e.g., m is 0 or m is 1). In some embodiments, k is 0. In some embodiments, m is 0, 1 or 2 (e.g., m is 0 or m is 1), and k is 0.
[0025] In some embodiments, R3a is hydrogen. [0026] In some embodiments, Ra is hydrogen or Ci-C4 alkyl (optionally substituted by 1 , 2 or 3 halogens). In certain embodiments, Ra is hydrogen.
[0027] In some embodiments, Rbi and Rb2 are each independently selected from the group consisting of hydrogen, hydroxyl, C^alkoxy (optionally substituted by one, two or three substituents independently selected from halogen and hydroxyl) and C1-C4 alkyl (optionally substituted by one, two or three substituents independently selected from halogen and hydroxyl). In certain embodiments, R i and Rb2 for each occurrence are hydrogen.
[0028] In some embodiments, R2 is selected from the group consisting of phenyl and a 5-6 membered heteroaryl having one or two heteroatoms each selected from N, S, and O, wherein R2 is optionally substituted by one or two substituents each independently selected from the group consisting of halogen, and Ci-C4 alkyl (optionally substituted by one, two or three halogens).
[0029] In certain embodiments, R2 is phenyl. In other embodiments, R2 is phenyl is substituted with one or two R5j wherein each R5 is independently selected from the group consisting of optionally substituted C1-C10 alkyl, optionally substituted C2-Ci0 alkenyl, optionally substituted C2-Cio alkynyl, and halo. In still other embodiments, R2 is a para- substituted phenyl. [0030] In other embodiments, R2 is selected from the group consisting of: optionally substituted thienyl, optionally substituted furanyl and optionally substituted pyridinyl.
[0031] In some embodiments, R4a is selected from the group consisting of optionally substituted CrC6 alkyl, optionally substituted C3-C7 cycloalkyl, phenyl, ORc, C(0)ORc, C(0)Rc, optionally substituted heterocycle and optionally substituted heteroaryl, wherein Rc is selected, independently for each occurrence, from the group consisting of H and Ci_6alkyl.
[0032] In certain embodiments, R4a is heterocycle, or a 5-6 membered monocyclic or a 8- 10 membered bicyclic heteroaryl having one, two or three heteroatoms selected from N, S or O, wherein the heterocycle or heteroaryl are optionally substituted by one, two or three substituents independently selected for each occurrence from the group consisting of halogen, Ci.6alkyl (optionally substituted by one, two or three substituents each independently selected from halogen and hydroxyl), Ci-6alkoxy (optionally substituted by one, two or three halogens), hydroxyl, and NR^Rd wherein R^ is independently for each occurrence selected from H and Q. 4alkyl, or the two R<jS taken together with the N to which they are attached form a heterocyclic ring). For example, R4a can be selected from the group consisting of tetrahydropyranyl, thiadiazolyl, tetrahydrofuranyl, and morpholinyl. As another example, R4a can be a monocyclic heteroaryl containing one, two or three ring nitrogen atoms. As a further example, R a can be selected from the group consisting of furanyl, pyridinyl, pyrazinyl, pyrazolyl, imidazolyl, isoxazolyl, triazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, thienyl, piperazinyl, and
benzimidazolyl, each optionally substituted.
[0033] In certain embodiments, R4a is selected from the group consisting of:
Figure imgf000017_0001
wherein each X is independently O, S or NRg;
each Rg is independently selected from the group consisting of hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl;
each R6_ R7 and R8 is independently selected for each occurrence from the group consisting of hydrogen, Ci-C6 alkyl, C2-C6 alkenyl, C2-Ci6 alkynyl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, phenyl, heterocycle, heteroaryl, halo, hydroxyl, carboxyl, ORc, NRdRd, C(0)ORc, CN, C(0)Rc, wherein the Ci-6alkyl, C2-C6 alkenyl, C2-C16 alkynyl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, phenyl, heterocycle, and heteroaryl of R6, R7 and R8 may each be optionally substituted by one, two or three substituents selected from halo, hydroxyl, Ci-6alkyl and Ci_ 6alkoxy;
Rc is C alkyl; and
Rd is independently for each occurrence selected from the group consisting of H and Q. 4alkyl, or the two RdS taken together with the N to which they are attached form a heterocyclic ring.
[0034] In certain embodiments, R^ is an optionally substituted C3-C7 cycloalkyl (e.g., optionally substituted cyclopropyl or an optionally substituted cyclobutyl). In certain of these embodiments, R4a is substituted with a substituent having the
Figure imgf000018_0001
wherein each Rh is independently selected for each occurrence from the group consisting of hydrogen, halo, hydroxyl, Ci-C6 alkyl, and C3-C6 cycloalkyl, or two geminal Rh groups are independently taken together with the carbon atom to which they are attached to form an optionally substituted carbocyclic or heterocycle;
R9 is selected from the group consisting of hydrogen, halo, CN, hydroxyl, methyl (optionally substituted by one, two or three substituents selected from halogen and hydroxyl), C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C^alkoxy, NRdRa, C(0)ORc, N02, CN,
C(0)Rc, C(0)C(0)Rc, CiC NRdRd, NRdC(0)Rc, NRdS(0)nRc, NRd(COORc), NRdC(0)C(0)Rc, RdC(0) RdRd, NRdS^nNRdRd, NRdS(0)nRc, S(0)„Rc, S(0)nNRdRd, OC(0)ORc, (C=NRd)Rc
Rc is independently selected for each occurrence from the group consisting of H, C1 -C6 alkyl, C3-6cycloalkyl, heterocycle, and heteroaryl;
Rd is independently selected for each occurrence from H and C|.4alkyl, or the two Rjs taken together with the N to which they are attached form a heterocyclic ring; and p is 0, 1 , or
2.
[0036] For example, R^ can be selected from the group consisting of:
Figure imgf000019_0001
wherein each Rio is independently selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C6 cycloalkyi, optionally substituted C3-C6 cycloalkenyl, optionally substituted aryl, halo, ORc, NRjRd, C(0)ORc, N02, CN, C(0)Rc, C(0)C(0)Rc, C(0)NRdRd, NRdC(0)Rc, N¾S(0)nRc, NRd(COORc), NRdC(0)C(0)Rc, Ν¾ϋ(0)Ν¾¾, NRdS^nNRdRd, NRdS(0)„Rc, S(0)nRc, S(0)nNR<jR<i, 00(0)0^, (C=NRd)Rc, optionally substituted heterocyclic and optionally substituted heteroaryl; alternatively, two geminal Rio groups are taken together with the carbon atom to which they are attached to form a spiro C3-C7 cycloalkyi, a spiro C3-C7 cycloalkenyl, a spiro heterocyclic, a spiro aryl or spiro heteroaryl, each optionally substituted; or yet alternatively, two vicinal Rio groups are taken together with the carbon atoms to which they are attached to form a fused, optionally substituted cyclic group selected from the group consisting of C4-C8 cycloalkyi, C4-C8 cycloalkenyl, 4- to 8-membered heterocyclic, aryl and heteroaryl, each optionally substituted; or further alternatively, two Rio groups attached to non-adjacent carbon atoms are taken together with the carbon atoms to which they are attached to form a bridged cyclic group selected from the group consisting of C3-C8 cycloalkyi, C3-C8 cycloalkenyl, and 4- to 8-membered heterocyclic, each optionally substituted; each Rh is independently selected from the group consisting of hydrogen, halo, optionally substituted Ci-Cio alkyl, and optionally substituted C3-C6 cycloalkyi, or two geminal Rb groups are independently taken together with the carbon atom to which they are attached to form an optionally substituted heterocyclic or an optionally substituted heteroaryl; R.9 is selected from the group consisting of hydrogen, optionally substituted Ci-C]0 alkyl, optionally substituted C2-Ci0 alkenyl, optionally substituted C2-Cio alkynyl, optionally substituted C3-Ci2 cycloalkyl, optionally substituted C3-C)2 cycloalkenyl, optionally substituted aryl, halo, ORc, NRdRd, C(0)ORc, N02, CN, C(0)Rc, C(0)C(0)Rc, CiC NRdRd, NRdC(0)Rc, NRdS(0)nRc, NRd(COORc), NRdC(0)C(0)Rc, NRcQC NRdRd, NRdS(0)nNRdR<), NRdS(0)nRc, S(0)nRc, SCC nNRdRd, OC(0)ORc, (C=NRd)Rc, optionally substituted heterocyclic and optionally substituted heteroaryl; and p is 0, 1, or 2.
[0037] In some embodiments, Y is S, S(0)2 or S(0)2NRd.
[0038] In some embodiments, R4b is heterocycle or a 5-6 membered monocyclic or a 8-10 membered bicyclic heteroaryl having one, two or three heteroatoms selected from N, S or O, wherein the heterocycle or heteroaryl are optionally substituted by one, two or three substituents independently selected for each occurrence from the group consisting of halogen, Ci.6alkyl (optionally substituted by one, two or three substituents each independently selected from halogen and hydroxyl), Ci-6alkoxy (optionally substituted by one, two or three halogens), hydroxyl, and NRdRd wherein Rd is independently for each occurrence selected from H and Q. 4alkyl, or the two R s taken together with the N to which they are attached form a heterocyclic ring). For example, R4b can be selected from the group consisting of furanyl, pyridinyl, pyrazinyl, pyrazolyl, imidazolyl, isoxazolyl, triazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, thienyl, piperazinyl, and benzimidazolyl, each optionally substituted. [0039] Exemplary compounds are shown below in Table 1 :
Table 1
Figure imgf000020_0001
Figure imgf000021_0001
[0040] Also contemplated herein are pharmaceutical compositions that include a disclosed compound such as those compounds having Formula (IVa), (Va), (IV), or (V) and a pharmaceutically acceptable carrier or excipient. In certain embodiments, the compositions can include at least one additional CFTR modulator as described anywhere herein or at least two additional CFTR modulators, each independently as described anywhere herein.
[0041] It is to be understood that the specific embodiments described herein can be taken in combination with other specific embodiments delineated herein. For example, as discussed above, in some embodiments, R2a is fluoro, and in some embodiments described above, A is an optionally substituted imidazolyl or pyrazolyl. The disclosure, in an embodiment, thus encompasses compound of Formula (IVa), (Va), (IV), or (V), wherein R2a is fluoro and A is an optionally substituted imidazolyl or pyrazolyl.
[0042] The features and other details of the disclosure will now be more particularly described. Before further description of the present invention, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and as understood by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art.
[0043] It will be appreciated that the description of the present invention herein should be construed in congruity with the laws and principals of chemical bonding. [0044] The term "alkyl", as used herein, unless otherwise indicated, refers to both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; for example, "CrCio alkyl" denotes alkyl having 1 to 10 carbon atoms, and straight or branched hydrocarbons of 1 -6, 1 -4, or 1 -3 carbon atoms, referred to herein as Ci_ 6alkyl, and Q alkyl, respectively. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, 2- methylbutyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl, and 4-methylpentyl. [0045] The term, "alkenyl", as used herein, refers to both straight and branched-chain moieties having the specified number of carbon atoms and having at least one carbon-carbon double bond. Exemplary alkenyl groups include, but are not limited to, a straight or branched group of 2-6 or 3-4 carbon atoms, referred to herein as C2-6alkenyl, and C3-4alkenyl, respectively. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, etc.
[0046] The term, "alkynyl", as used herein, refers to both straight and branched-chain moieties having the specified number or carbon atoms and having at least one carbon-carbon triple bond.
[0047] The term "cycloalkyl," as used herein, refers to saturated cyclic alkyl moieties having 3 or more carbon atoms, for example, 3-10, 3-6, or 4-6 carbons, referred to herein as C3- locycloalkyl, C3-6cycloalkyl or C4-6cycloalkyl, respectively for example. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and adamantyl.
[0048] The term "cycloalkenyl," as used herein, refers to cyclic alkenyl moieties having 3 or more carbon atoms.
[0049] The term "cycloalkynyl," as used herein, refers to cyclic alkynyl moieties having 5 or more carbon atoms.
[0050] "Alkylene" means a straight or branched, saturated aliphatic divalent radical having the number of carbons indicated. "Cycloalkylene" refers to a divalent radical of carbocyclic saturated hydrocarbon group having the number of carbons indicated.
[0051] The term "alkoxy" as used herein refers to a straight or branched alkyl group attached to oxygen (alkyl-O-). Exemplary alkoxy groups include, but are not limited to, alkoxy groups of 1 -6 or 2-6 carbon atoms, referred to herein as Ci-ealkoxy, and C2-6alkoxy,
respectively. Exemplary alkoxy groups include, but are not limited to methoxy, ethoxy, isopropoxy, etc. [0052] The term "heterocyclic" or "heterocycle" encompasses heterocycloalkyl, heterocycloalkenyl, heterobicycloalkyl, heterobicycloalkenyl, heteropolycycloalkyl, heteropolycycloalkenyl, and the like unless indicated otherwise. Heterocycloalkyl refers to cycloalkyl groups containing one or more heteroatoms (O, S, or N) within the ring.
Heterocycloalkenyl as used herein refers to cycloalkenyl groups containing one or more heteroatoms (O, S or N) within the ring. Heterobicycloalkyl refers to bicycloalkyl groups containing one or more heteroatoms (O, S or N) within a ring. Heterobicycloalkenyl as used herein refers to bicycloalkenyl groups containing one or more heteroatoms (O, S or N) within a ring. A heterocycle can refer to, for example, a saturated or partially unsaturated 4- to 12 or 4- 10-membered ring structure, including bridged or fused rings, and whose ring structures include one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Where possible, heterocyclic rings may be linked to the adjacent radical through carbon or nitrogen. Examples of heterocyclic groups include, but are not limited to, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxetane, azetidine, tetrahydrofuran or dihydrofuran, etc. [0053] Cycloalkyl, cycloalkenyl, and heterocyclic groups also include groups similar to those described above for each of these respective categories, but which are substituted with one or more oxo moieties.
[0054] The term "aryl", as used herein, refers to mono- or polycyclic aromatic carbocyclic ring systems. A polycyclic aryl is a polycyclic ring system that comprises at least one aromatic ring. Polycyclic aryls can comprise fused rings, covalently attached rings or a combination thereof. The term "aryl" embraces aromatic radicals, such as, phenyl, naphthyl, indenyl, tetrahydronaphthyl, and indanyl. An aryl group may be substituted or unsubstituted. In some embodiments, the aryl is a C4-C10 aryl. Examples of optionally substituted aryl are phenyl, substituted phenyl, naphthyl and substituted naphthyl. [0055] The term "heteroaryl", as used herein, refers to aromatic carbocyclic groups containing one or more heteroatoms (O, S, or N) within a ring. A heteroaryl group, unless indicated otherwise, can be monocyclic or polycyclic. A heteroaryl group may additionally be substituted or unsubstituted. Heteroaryl groups can also include ring systems substituted with one or more oxo moieties. A polycyclic heteroaryl can comprise fused rings, covalently attached rings or a combination thereof. A polycyclic heteroaryl is a polycyclic ring system that comprises at least one aromatic ring containing one or more heteroatoms within a ring. Examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, triazinyl, isoindolyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, dihydroquinolyl, tetrahydroquinolyl, dihydroisoquinolyl, tetrahydroisoquinolyl, benzofuryl, furopyridinyl, pyrolopyrimidinyl, thiazolopyridinyl, oxazolopyridinyl and azaindolyl. The foregoing heteroaryl groups may be C-attached or heteroatom-attached (where such is possible). For instance, a group derived from pyrrole may be pyrrol- 1-yl (N-attached) or pyrrol-3-yl (C-attached). In some embodiments, the heteroaryl is 4- to 12-membered heteroaryl. In yet other embodiments, the heteroaryl is a mono or bicyclic 4- to 10-membered heteroaryl.
[0056] The term "substituted" refers to substitution by independent replacement of one, two, or three or more of the hydrogen atoms with substituents including, but not limited to, and unless indicated otherwise, -Ci-Ci2 alkyl, -C2-Ci2 alkenyl, -C2-Ci2 alkynyl, -C3-Ci2 cycloalkyl, -C3-C,2 cycloalkenyl, C3-C,2 cycloalkynyl, -heterocyclic, -F, -CI, -Br, -I, -OH, -N02, -N3, -CN, -NH2, oxo, thioxo, -NHRX, -NRXRX, dialkylamino, -diarylamino, -diheteroarylamino, -ORx, - C(0)Ry, -C(0)C(0)Ry, -OC02Ry, -OC(0)Ry, OC(0)C(0)Ry, -NHC(0)Ry, -NHC02Ry, - NHC(0)C(0)Ry, NHC(S)NH2, -NHC(S)NHRX, -NHC(NH)NH2, -NHC(NH)NHRX, - NHC(NH)RX, -C(NH)NHRX, and (C=NRX)RX; -NRxC(0)Rx, -NRxC(0)N(Rx)2, -NRxC02Ry, - NRxC(0)C(0)Ry, -NRXC(S)NH2, -NRXC(S)NHRX, -NRXC(NH)NH2, -NRXC(NH)NHRX, -
NRXC(NH)RX, -C(NRx)NHRx -S(0)Ry, -NHS02Rx, -CH2NH2, -CH2S02CH3, -aryl, -arylalkyl, - heteroaryl, -heteroarylalkyl, -heterocycloalkyl, -C3-Ci2-cycloalkyl, -polyalkoxyalkyl, - polyalkoxy, -methoxymethoxy, -methoxyethoxy, -SH, -S-Rx, or -methylthiomethyl, wherein Rx is selected from the group consisting of hydrogen, -Ci-Ci2 alkyl, -C2-C) alkenyl, -C2-C]2 alkynyl, -C3-Ci2 cycloalkyl, -aryl, -heteroaryl and -heterocyclic and -Ry is selected from the group consisting of hydrogen, -C1-C12 alkyl, -C2-Ci2 alkenyl, -C2-Ci2 alkynyl, -C3-Ci2 cycloalkyl, -aryl, -heteroaryl, -heterocyclic, -NH2, -NH-C1 -C 12 alkyl, -NH-C2-C 12 alkenyl, -NH- C2-C i2-alkynyl, -NH-C3-C 12 cycloalkyl, -NH-aryl, -NH-heteroaryl and -NH-heterocyclic. It is understood that the aryls, heteroaryls, alkyls, and the like can be further substituted.
[0057] The terms "halo" or "halogen" as used herein refer to F, CI, Br, or I.
[0058] The term "haloalkyl" as used herein refers to an alkyl group having 1 to (2n+l) substituent(s) independently selected from F, CI, Br or I, where n is the maximum number of carbon atoms in the alkyl group. It will be understood that haloalkyl is a specific example of an optionally substituted alkyl.
[0059] The terms "hydroxy" and "hydroxyl" as used herein refers to the radical -OH.
[0060] As will be understood by the skilled artisan, "H" is the symbol for hydrogen, "N" is the symbol for nitrogen, "S" is the symbol for sulfur, and "O" is the symbol for oxygen. "Me" is an abbreviation for methyl. [0061] The compounds of the disclosure may contain one or more chiral centers and, therefore, exist as stereoisomers. The term "stereoisomers" when used herein consist of all enantiomers or diastereomers. These compounds may be designated by the symbols "(+)," "(- )," or "S," depending on the configuration of substituents around the stereogenic carbon atom, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated "(±)" in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.
[0062] The compounds of the disclosure may contain one or more double bonds and, therefore, exist as geometric isomers resulting from the arrangement of substituents around a carbon-carbon double bond. The symbol = denotes a bond that may be a single, double or triple bond as described herein. Substituents around a carbon-carbon double bond are designated as being in the "Z" or configuration wherein the terms "Z" and "E" are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the "E " and "Z" isomers. Substituents around a carbon-carbon double bond alternatively can be referred to as "cis" or "trans," where "cis" represents substituents on the same side of the double bond and "trans" represents substituents on opposite sides of the double bond.
[0063] Compounds of the disclosure may contain a carbocyclic or heterocyclic ring and therefore, exist as geometric isomers resulting from the arrangement of substituents around the ring. The arrangement of substituents around a carbocyclic or heterocyclic ring are designated as being in the "Z" or "E " configuration wherein the terms "Z" and "E " are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting carbocyclic or heterocyclic rings encompass both "Z" and "E" isomers. Substituents around a carbocyclic or heterocyclic ring may also be referred to as "cis" or "trans", where the term "cis" represents substituents on the same side of the plane of the ring and the term "trans" represents substituents on opposite sides of the plane of the ring. Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated "cis/trans."
[0064] Individual enantiomers and diasterisomers of compounds of the present disclosure can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1 ) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, (3) direct separation of the mixture of optical enantiomers on chiral liquid chromatographic columns or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved into their component enantiomers by well known methods, such as chiral-phase liquid chromatography or crystallizing the compound in a chiral solvent. Stereoselective syntheses, a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a pre-existing one, are well known in the art. Stereoselective syntheses encompass both enantio- and diastereoselective transformations, and may involve the use of chiral auxiliaries. For examples, see Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley- VCH: Weinheim, 2009. Where a particular compound is described or depicted, it is intended to encompass that chemical structure as well as tautomers of that structure. [0065] The term "enantiomerically pure" means a stereomerically pure composition of a compound. For example, a stereochemical ly pure composition is a composition that is free or substantially free of other stereoisomers of that compound. In another example, for a compound having one chiral center, an enantiomerically pure composition of the compound is free or substantially free of the other enantiomer. In yet another example, for a compound having two chiral centers, an enantiomerically pure composition is free or substantially free of the other diastereomers.
[0066] Where a particular stereochemistry is described or depicted it is intended to mean that a particular enantiomer is present in excess relative to the other enantiomer. A compound has an R-configuration at a specific position when it is present in excess compared to the compound having an S-configuration at that position. A compound has an S-configuration at a specific position when it is present in excess compared to the compound having an R- configuration at that position.
[0067] The compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that disclosed compounds include both solvated and unsolvated forms. In one embodiment, a disclosed compound is amorphous or, in another embodiment, a single polymorph. In another embodiment, a disclosed compound is a mixture of polymorphs. In another embodiment, a disclosed compound is in a crystalline form. [0068] Isotopically labeled compounds are also contemplated herein, which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2H, 3H, 13C, ,4C, 1 SN, l80, l70, 31P, 32P, 35S, l8F, and 36C1, respectively. For example, a disclosed compound may have one or more H atom replaced with deuterium.
[0069] Certain isotopically-labeled disclosed compounds (e.g., those labeled with 3H and l4C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3H) and carbon- 14 (i.e., 14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed in the examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
[0070] In some embodiments one or more of the nitrogen atoms of a disclosed compound if present are oxidized to N-oxide.
[0071] Representative synthetic routes for the preparation of the compounds disclosed herein are provided throughout the Examples section. As will be understood by the skilled artisan, diastereomers can be separated from the reaction mixture using column
chromatography.
[0072] Compounds of the invention can also be prepared using methods described in the literature, including, but not limited to, J. Med. Chem. 2011, 54(13), 4350-64; Russian Journal of Organic Chemistry, 201 1 , 47(8), 1 199-1203; U.S. Patent Application Publication No.
2009/0036451 Al ; WO2008/046072 A2, and U.S. Patent No. 4,336,264, the contents of each of which are expressly incorporated by reference herein. [0073] As discussed above, the invention encompasses a method of enhancing (e.g., increasing) CFTR activity in a subject (e.g., a subject suffering from any one or more of the conditions described herein) comprising administering a compound of the invention in an effective amount. The invention also encompasses a method of treating a patient suffering from a condition associated with CFTR activity comprising administering to said patient an effective amount of a compound described herein. In certain embodiments, the disease is cystic fibrosis.
[0074] "Treating" or "treatment" includes preventing or delaying the onset of the symptoms, complications, or biochemical indicia of a disease, alleviating or ameliorating the symptoms or arresting or inhibiting further development of the disease, condition, or disorder. A "subject" is an animal to be treated or in need of treatment. A "patient" is a human subject in need of treatment.
[0075] An "effective amount" refers to that amount of an agent that is sufficient to achieve a desired and/or recited effect. In the context of a method of treatment, an "effective amount" of the therapeutic agent that is sufficient to ameliorate of one or more symptoms of a disorder and/or prevent advancement of a disorder, cause regression of the disorder and/or to achieve a desired effect.
[0076] The term "modulating" encompasses increasing, enhancing, inhibiting, decreasing, suppressing, and the like. The terms "increasing" and "enhancing" mean to cause a net gain by either direct or indirect means. As used herein, the terms "inhibiting" and "decreasing" encompass causing a net decrease by either direct or indirect means.
[0077] In some examples, CFTR activity is enhanced after administration of a compound described herein when there is an increase in the CFTR activity as compared to that in the absence of the administration of the compound. CFTR activity encompasses, for example, chloride channel activity of the CFTR, and/or other ion transport activity (for example, HCO3 " transport). In certain of these embodiments, the activity of one or more (e.g., one or two) mutant CFTRs (e.g., AF508, S549N, G542X, G551 D, Rl 17H, N1303 , W1282X, R553X, 621+lOT, 1717-l OA, 3849+l OkbOT, 2789+50A, 3120+1OA, I507del, R1 162X, 1898+1G>A, 3659delC, G85E, D1 152H, R560T, R347P, 2184insA, A455E, R334W, Q493X, and 2184delA CFTR) is enhanced (e.g., increased). Contemplated patients may have a CFTR mutation(s) from one or more classes, such as without limitation, Class I CFTR mutations, Class II CFTR mutations, Class III CFTR mutations, Class IV CFTR mutations, Class V CFTR mutations, and Class VI mutations. Contemplated subject (e.g., human subject) CFTR genotypes include, without limitation, homozygote mutations (e.g., AF508 / AF508 and Rl 17H / Rl 17H) and compound heterozygote mutations (e.g., AF508 / G551D; AF508 / A455E;
AF508 / G542X; A508F / Wl 204X; R553X / Wl 316X; Wl 282X/N 1303K, 591 Δ18 / E831 X, F508del/Rl 17H/ N1303 / 3849+10kbC>T; Δ303Κ/ 384; and DF508/G 178R).
[0078] In certain embodiments, the mutation is a Class I mutation, e.g., a G542X; a Class II/ 1 mutation, e.g., a AF508 / G542X compound heterozygous mutation. In other
embodiments, the mutation is a Class III mutation, e.g., a G551D; a Class II/ Class III mutation, e.g., a AF508 / G551 D compound heterozygous mutation. In still other embodiments, the mutation is a Class V mutation, e.g., a A455E; Class II/ Class V mutation, e.g., a AF508 / A455E compound heterozygous mutation. Of the more than 1000 known mutations of the CFTR gene, AF508 is the most prevalent mutation of CFTR which results in misfolding of the protein and impaired trafficking from the endoplasmic reticulum to the apical membrane (Dormer et al. (2001). J Cell Sci 1 14, 4073-4081 ; http://www.genet.sickkids.on.ca/app). In certain embodiments, AF508 CFTR activity is enhanced (e.g., increased). In certain
embodiments, AF508 CFTR activity and/or G542X CFTR activity and/or G551 D CFTR activity and/or A455E CFTR activity is enhanced (e.g., increased). An enhancement of CFTR activity can be measured, for example, using. literature described methods, including for example, Ussing chamber assays, patch clamp assays, and hBE Ieq assay (Devor et al. (2000), Am J Physiol Cell Physiol 279(2): C461-79; Dousmanis et al. (2002), J Gen Physiol 1 19(6): 545-59; Bruscia et al. (2005), PNAS 103(8): 2965-2971 ).
[0079] As discussed above, a method of treating cystic fibrosis is provided herein comprising administering a disclosed compound. Disclosed methods can also be used to treat other conditions associated with CFTR activity, including conditions associated with deficient CFTR activity.
[0080] In some embodiments, a method of treating a condition associated with deficient or decreased CFTR activity is provided comprising administering an effective amount of a compound of Formula (IV a) or (Va) or (IV) or (V) that enhances CFTR activity. Non-limiting examples of conditions associated with deficient CFTR activity are cystic fibrosis, congenital bilateral absence of vas deferens (CBAVD), acute, recurrent, or chronic pancreatitis, disseminated bronchiectasis, asthma, allergic pulmonary aspergillosis, smoking-related lung diseases, such as chronic obstructive pulmonary disease (COPD), chronic sinusitis, dry eye disease, protein C deficiency, Αβ-lipoproteinemia, lysosomal storage disease, type 1 chylomicronemia, mild pulmonary disease, lipid processing deficiencies, type 1 hereditary angioedema, coagulation-fibrinolyis, hereditary hemochromatosis, CFTR-related metabolic syndrome, chronic bronchitis, constipation, pancreatic insufficiency, hereditary emphysema, and Sjogren's syndrome. [0081] In some embodiments, disclosed methods of treatment further comprise
administering an additional therapeutic agent. For example, in an embodiment, provided herein is a method of administering a disclosed compound and at least one additional therapeutic agent. In certain aspects, a disclosed method of treatment comprises administering a disclosed compound, and at least two additional therapeutic agents. Additional therapeutic agents include, for example, mucolytic agents, bronchodilators, antibiotics, anti-infective agents, antiinflammatory agents, ion channel modulating agents, therapeutic agents used in gene therapy, CFTR correctors, and CFTR potentiators, or other agents that modulates CFTR activity. In some embodiments, at least one additional therapeutic agent is selected from the group consisting of a CFTR corrector and a CFTR potentiator. Non-limiting examples of CFTR correctors and potentiators include VX-770 (I vacaftor), VX-809 (3-(6-( 1 -(2,2- difluorobenzo[d][l ,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, VX-661 (l-(2,2-difluoro- l ,3-benzodioxol-5-yl)-N-[l -[(2R)-2,3-dihydroxypropyl]-6- fluoro-2-(2-hydroxy-l, l -dimethylethyl)-lH-indol-5-yl]- cyclopropanecarboxamide), VX-983, VX-152, VX-440, and Ataluren (PTC124) (3-[5-(2-fluorophenyl)-l ,2,4-oxadiazol-3-yl]benzoic acid), FDL 169, GLPG1837/ABBV-974 (for example, a CFTR potentiator), GLPG 2665, GLPG2222 (for example, a CFTR corrector); and compounds described in, e.g.,
WO2014/144860 and 2014/176553, hereby incorporated by reference. Non-limiting examples of modulators include QBW-251, QR-010, NB-124, and compounds described in, e.g.,
WO2014/045283; WO2014/081821 , WO2014/081820, WO2014/152213; WO2014/160440, WO2014/160478, US2014027933; WO2014/0228376, WO2013/038390,
WO201 1/1 13894, WO2013/038386; and WO2014/ 180562, of which the disclosed modulators in those publications are contemplated as an additional therapeutic agent and incorporated by reference. Non-limiting examples of anti-inflammatory agents include N6022 (3-(5-(4-(lH- imidazol-l -yl) phenyl)-l -(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl) propanoic acid), ~ CTX-4430, N1861, N1785, and N91 1 15.
[0082] In some embodiments, the methods described herein can further include
administering an additional therapeutic agent or administering at least two additional CFTR therapeutic agents. In some embodiments, the methods described herein can further include administering an additional CFTR modulator or administering at least two additional CFTR modulators. In certain embodiments, at least one CFTR modulator is a CFTR corrector (e.g., VX-809, VX-661 , VX-983, VX-152, VX-440, GLPG2222 and GLPG2665) or potentiator (e.g., ivacaftor, genistein and GLPG 1837). In certain of these embodiments, one of the at least two additional therapeutic agents is a CFTR corrector (e.g., VX-809, VX-661 , VX-983, VX-152, and VX-440) and the other is a CFTR potentiator (e.g., ivacaftor and genistein). In certain of these embodiments, one of the at least two additional therapeutic agents is a CFTR corrector (e.g., GLPG2222 or GLPG2665) and the other is a CFTR potentiator (e.g., GLPG 1837). In certain of these embodiments, one of the at least two additional therapeutic agents is a CFTR corrector (e.g., VX-809 or VX-661) and the other is a CFTR potentiator (e.g., ivacaftor). In certain of these embodiments, at least one CFTR modulator is an agent that enhances read- through of stop codons (e.g., NB 124 or ataluren). [0083] Accordingly, in another aspect, this disclosure provides a method of treating a condition associated with deficient or decreased CFTR activity (e.g., cystic fibrosis), which includes administering to a subject in need thereof (e.g., a human patient in need thereof) an effective amount of a disclosed compound and at least one or two additional CFTR therapeutic agent(s) (e.g., at least one or two additional CFTR therapeutic agents, e.g., in which one of the at least one or two additional therapeutic agents is optionally a CFTR corrector or modulator (e.g., VX-809, VX-661, VX-983, VX-152, VX-440, GLPG2222, GLPG2665, NB124, ataluren) and/or the other is a CFTR potentiator (e.g., ivacaftor, genistein, and GLPG 1837); e.g., one of the at least two additional therapeutic agents is GLPG2222 or GLPG2665, and the other is GLPG1837; or one of the at least two additional therapeutic agents is VX-809 or VX-661 , and the other is ivacaftor. In certain embodiments, the subject's CFTR genotype includes, without limitation, one or more Class I CFTR mutations, one or more Class II CFTR mutations, one or more Class III CFTR mutations, one or more Class IV CFTR mutations, or one or more Class V CFTR mutations, or one or more Class VI CFTR mutations. In certain embodiments, the subject's CFTR genotype includes, without limitation, one or more homozygote mutations (e.g., AF508 / AF508 or Rl 17H / Rl 17H) and/or one or more compound heterozygote mutations (e.g., AF508 / G551D; AF508 / A455E; AF508 / G542X; A508F / W1204X; R553X / W 1316X; Wl 282X/N 1303K; F508del/Rl 17H; N 1303K/ 3849+1 OkbOT; AF508/R334 W; DF508/G178R, and 591 Δ18 / E831X). In certain embodiments, the subject's CFTR genotype includes a Class I mutation, e.g., a G542X Class 1 mutation, e.g., a AF508 / G542X compound heterozygous mutation. In other embodiments, the subject's CFTR genotype includes a Class III mutation, e.g., a G551 D Class III mutation, e.g., a AF508 / G551D compound heterozygous mutation. In still other embodiments, the subject's CFTR genotype includes a Class V mutation, e.g., a A455E Class V mutation, e.g., a AF508 / A455E compound heterozygous mutation. In certain embodiments, AF508 CFTR activity and/or G542X CFTR activity and/or G55 ID CFTR activity and/or A455E activity is enhanced (e.g., increased). In certain embodiments, the enhancement in activity (e.g., increase in activity) provided by the combination of the disclosed compound and one or two additional therapeutic agents is greater than additive when compared to the enhancement in activity provided by each therapeutic component individually.
Figure imgf000035_0001
Figure imgf000035_0002
R553X and W1316X compound heterozygote Mild lung disease,
pancreatic insufficient
591Δ18 / Ε831Χ compound heterozygote No lung or pancreas disease, nasal polyps
[0084] For example, provided herein is a method of treating a patient having one or more of the following mutations in the CFTR gene: G1244E, G1349D, G178R, G551S, SI 25 IN, S1255P, S549N, S549R , G970R, or R117H, and/or e.g., a patient with one or two copies of the F508del mutation, or one copy of the AF508 mutation and a second mutation that results in a gating effect in the CFTR protein (e.g., a patient that is heterozygous for AF508 and G55 ID mutation), a patient with one copy of the AF508 mutation and a second mutation that results in residual CFTR activity, or a patient with one copy of the AF508 mutation and a second mutation that results in residual CFTR activity, comprising administering an effective amount of a disclosed compound. As described herein, such exemplary methods (e.g., of a patient having one or mutations such as those described above) may include, for example,
administering to such patient a combination therapy, e.g., administering (simultaneously or sequentially) an effective amount of ivacaftor to said patient and an effective amount of disclosed compound that may act as an amplifier. Such administration may result, for example, in increased chloride transport in human bronchial epithelial cells with e.g., one or two copies of mutations, e.g, AF508 mutation, as compared to administration of ivacaftor alone. Another combination therapy that includes a disclosed compound may also include an effective amount of a readthrough agent (e.g., ataluren, NB 124) and an effect amount of disclosed compound that may act as an amplifier. [0085] The phrase "combination therapy," as used herein, refers to an embodiment where a patient is co-administered a disclosed compound, a CFTR potentiator agent (e.g., ivacaftor) and optionally, one or more CFTR corrector agent(s) (e.g, VX-661 and/or lumacaftor) as part of a specific treatment regimen intended to provide the beneficial effect from the co-action of these therapeutic agents. For example, a beneficial effect of a combination may include, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents. For example, administration of a disclosed compound with ivacaftor alone or with a CFTR corrector agent (e.g., lumacaftor or VX-661) may result in a level of function (e.g., as measured by chloride activity in HBE cells or patients that have a AF508 mutation, that achieves clinical improvement (or better) as compared to the chloride activity level in cells or patients with a G55 ID mutation receiving ivacaftor alone, or ivacaftor and a corrector agent (lumacaftor or VX-661); or for example, administration of a disclosed compound with ivacaftor alone or ivacaftor with a CFTR corrector agent (e.g., lumacaftor or VX-661) may result in a level of function (e.g., as measured by chloride activity in HBE cells or patients that have a A455E mutation, that achieves clinical improvement (or better) as compared to the chloride activity level at e.g., 50% or more of wild type cells; or upon administration of a disclosed compound and ivacaftor to a patient (e.g. having a G551D class III mutation) may show e.g., about two times or more improved activity of ivacaftor as compared to administration of ivacaftor alone. Administration of disclosed therapeutic agents in combination typically is carried out over a defined time period (usually a day, days, weeks, months or years depending upon the combination selected). Combination therapy is intended to embrace administration of multiple therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner. Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single tablet or capsule having a fixed ratio of each therapeutic agent or in multiple, single capsules for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, inhalational routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be
administered by the same route or by different routes. For example, a first therapeutic agent of the combination selected may be administered by intravenous injection or inhalation or nebulizer while the other therapeutic agents of the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection, inhalation or nebulization.
[0086] Combination therapy also can embrace the administration of the therapeutic agents as described above in further combination with other biologically active ingredients and non- drug therapies. Where the combination therapy further comprises a non-drug treatment, the non-drug treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and non-drug treatment is achieved. For example, in appropriate cases, the beneficial effect is still achieved when the non-drug treatment is temporally removed from the administration of the therapeutic agents, perhaps by a day, days or even weeks.
[0087] The components of a disclosed combination may be administered to a patient simultaneously or sequentially. It will be appreciated that the components may be present in the same pharmaceutically acceptable carrier and, therefore, are administered simultaneously. Alternatively, the active ingredients may be present in separate pharmaceutical carriers, such as, conventional oral dosage forms, that can be administered either simultaneously or sequentially.
[0088] In a further aspect, a method of identifying a candidate agent that increases CFTR activity is provided, which includes: (i) contacting a cell that expresses a CFTR protein with the candidate agent and a disclosed compound; (ii) measuring the CFTR activity in the cell in the presence of the candidate agent and the disclosed compound; and (iii) comparing the CFTR activity to that in the absence of the test agent, wherein an increase in CFTR activity in the presence of the test agent indicates that the agent increases CFTR activity. In certain embodiments, the cell expresses a mutant CFTR protein. In certain embodiments, CFTR activity is measured by measuring chloride channel activity of the CFTR, and/or other ion transport activity. In certain of these embodiments, the method is high-throughput. In certain of these embodiments, the candidate agent is a CFTR corrector or a CFTR potentiator. [0089] The term "pharmaceutically acceptable salt(s)" as used herein refers to salts of acidic or basic groups that may be present in a disclosed compounds used in disclosed compositions. Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing
pharmacologically acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, /?-toluenesulfonate and pamoate (i.e., l, l'-methylene-6 s-(2-hydroxy-3-naphthoate)) salts. Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. Compounds included in the present compositions that include a basic or acidic moiety may also form pharmaceutically acceptable salts with various amino acids. The compounds of the disclosure may contain both acidic and basic groups; for example, one amino and one carboxylic acid group. In such a case, the compound can exist as an acid addition salt, a zwitterion, or a base salt.
[0090] Also contemplated herein are methods that include administering prodrugs of the compounds described herein, for example, prodrugs of a compound of Formula (IVa) or (Va) or (IV) or (V), or a pharmaceutical composition thereof or method of use of the prodrug.
[0091] The term "prodrug" refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (such as by esterase, amidase, phosphatase, oxidative and or reductive metabolism) in various locations (such as in the intestinal lumen or upon transit of the intestine, blood or liver). Prodrugs are well known in the art (for example, see Rautio, umpulainen, et al, Nature Reviews Drug Discovery 2008, 7, 255). For example, if a compound of the invention or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as (Ci-g)alkyl, (C2.i2)alkylcarbonyloxymethyl, l -(alkylcarbonyloxy)ethyl having from 4 to 9 carbon atoms, 1 -methyl- l-(alkylcarbonyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl-l - (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1 -(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(C|.
2)alkylamino(C2-3)alkyl (such as β-dimethylaminoethyl), carbamoyl-(Ci-2)alkyl, N,N-di(Ci_ 2)alkylcarbamoyl-(Ci-2)alkyl and piperidino-, pyrrolidino- or morpholino(C2-3)alkyI.
[0092] Similarly, if a compound of the invention contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (Ci-6)aIkylcarbonyloxymethyl, l -((Ci-6)alkylcarbonyloxy)ethyl, 1 -methyl- l -((Ci. 6)alkylcarbonyloxy)ethyl (Ci-6)alkoxycarbonyloxymethyl, N-(Ci.
6)alkoxycarbonylaminomethyl, succinoyl, (Chalky lcarbonyl,
Figure imgf000040_0001
arylalkylcarbonyl and a-aminoalkylcarbonyl, or a-aminoalkylcarbonyl-a-aminoalkylcarbonyl, where each a-aminoalkylcarbonyl group is independently selected from the naturally occurring L-amino acids, P(0)(OH)2, -P(0)(0(Ci-6)alkyl)2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate).
[0093] If a compound of the invention incorporates an amine functional group, a prodrug can be formed, for example, by creation of an amide or carbamate, an N-alkylcarbonyloxyalkyl derivative, an (oxodioxolenyl)methyl derivative, an N-Mannich base, imine or enamine. In addition, a secondary amine can be metabolically cleaved to generate a bioactive primary amine, or a tertiary amine can metabolically cleaved to generate a bioactive primary or secondary amine. For examples, see Simplicio, et al, Molecules 2008, 13, 519 and references therein
[0094] Also contemplated in certain embodiments is the use of clathrates of the compounds described herein, pharmaceutical compositions comprising the clathrates, and methods of use of the clathrates. Clathrates of a disclosed compound or a pharmaceutical composition thereof are also contemplated herein.
[0095] As discussed above, the disclosure also contemplates administration of
pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and a compound described herein. A disclosed compound, or a pharmaceutically acceptable salt, solvate, clathrate or prodrug therof, can be administered in pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient. The excipient can be chosen based on the expected route of administration of the composition in therapeutic applications. The route of administration of the composition depends on the condition to be treated. For example, intravenous injection may be preferred for treatment of a systemic disorder and oral administration may be preferred to treat a gastrointestinal disorder. The route of administration and the dosage of the composition to be administered can be determined by the skilled artisan without undue experimentation in conjunction with standard dose-response studies. Relevant circumstances to be considered in making those determinations include the condition or conditions to be treated, the choice of composition to be administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms. A
pharmaceutical composition comprising a disclosed compound or a pharmaceutically acceptable salt, solvate, clathrate or prodrug, can be administered by a variety of routes including, but not limited to, parenteral, oral, pulmonary, ophthalmic, nasal, rectal, vaginal, aural, topical, buccal, transdermal, intravenous, intramuscular, subcutaneous, intradermal, intraocular, intracerebral, intralymphatic, intraarticular, intrathecal and intraperitoneal. The compositions can also include, depending on the formulation desired, pharmaceutical Iy- acceptable, non-toxic carriers or diluents, which are defined as vehicles commonly used to formulate pharmaceutical compositions for animal or human administration. The diluent is selected so as not to affect the biological activity of the pharmacologic agent or composition. Examples of such diluents are distilled water, physiological phosphate-buffered saline, Ringer's solutions, dextrose solution, and Hank's solution. In addition, the pharmaceutical composition or formulation may also include other carriers, adjuvants, or nontoxic, nontherapeutic, nonimmunogenic stabilizers and the like. Pharmaceutical compositions can also include large, slowly metabolized macromolecules such as proteins, polysaccharides such as chitosan, polylactic acids, polyglycolic acids and copolymers (such as latex functionalized
SEPHAROSE™, agarose, cellulose, and the like), polymeric amino acids, amino acid copolymers, and lipid aggregates (such as oil droplets or liposomes). [0096] Disclosed compositions can be administered parenterally such as, for example, by intravenous, intramuscular, intrathecal or subcutaneous injection. Parenteral administration can be accomplished by incorporating a composition into a solution or suspension. Such solutions or suspensions may also include sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents.
Parenteral formulations may also include antibacterial agents such as, for example, benzyl alcohol or methyl parabens, antioxidants such as, for example, ascorbic acid or sodium bisulfite and chelating agents such as EDTA. Buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose may also be added. The parenteral preparation can be enclosed in ampules, disposable syringes or multiple dose vials made of glass or plasticAdditionally, auxiliary substances, such as wetting or emulsifying agents, surfactants, pH buffering substances and the like can be present in compositions. Other components of pharmaceutical compositions are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, and mineral oil. In general, glycols such as propylene glycol or polyethylene glycol are preferred liquid carriers, particularly for injectable solutions.
[0097] Injectable formulations can be prepared either as liquid solutions or suspensions; solid forms suitable for solution in, or suspension in, liquid vehicles prior to injection can also be prepared. The preparation also can also be emulsified or encapsulated in liposomes or micro particles such as polylactide, polyglycolide, or copolymer for enhanced adjuvant effect, as 5 000211
discussed above [Langer, Science 249: 1527, 1990 and Hanes, Advanced Drug Delivery Reviews 28: 97- 1 19, 1997]. The compositions and pharmacologic agents described herein can be administered in the form of a depot injection or implant preparation which can be formulated in such a manner as to permit a sustained or pulsatile release of the active ingredient.
[0098] Additional formulations suitable for other modes of administration include oral, intranasal, and pulmonary formulations, suppositories, transdermal applications and ocular delivery. For suppositories, binders and carriers include, for example, polyalkylene glycols or triglycerides; such suppositories can be formed from mixtures containing the active ingredient in the range of about 0.5% to about 10%, preferably about 1% to about 2%. Oral formulations include excipients, such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, and magnesium carbonate. Topical application can result in transdermal or intradermal delivery. Transdermal delivery can be achieved using a skin patch or using transferosomes. [Paul et al., Eur. J. Immunol. 25: 3521 -24, 1995; Cevc et al., Biochem. Biophys. Acta 1368: 201 -15, 1998].
[0099] For the purpose of oral therapeutic administration, the pharmaceutical compositions can be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like. Tablets, pills, capsules, troches and the like may also contain binders, excipients, disintegrating agent, lubricants, glidants, sweetening agents, and flavoring agents. Some examples of binders include microcrystalline cellulose, gum tragacanth or gelatin. Examples of excipients include starch or lactose. Some examples of disintegrating agents include alginic acid, corn starch and the like. Examples of lubricants include magnesium stearate or potassium stearate. An example of a glidant is colloidal silicon dioxide. Some examples of sweetening agents include sucrose, saccharin and the like. Examples of flavoring agents include peppermint, methyl salicylate, orange flavoring and the like. Materials used in preparing these various compositions should be
pharmaceutically pure and non-toxic in the amounts used. In another embodiment, the composition is administered as a tablet or a capsule. [0100] Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor, and the like. For vaginal administration, a pharmaceutical composition may be presented as pessaries, tampons, creams, gels, pastes, foams or spray.
[0101] The pharmaceutical composition can also be administered by nasal administration. As used herein, nasally administering or nasal administration includes administering the composition to the mucus membranes of the nasal passage or nasal cavity of the patient. As used herein, pharmaceutical compositions for nasal administration of a composition include therapeutically effective amounts of the compounds prepared by well-known methods to be administered, for example, as a nasal spray, nasal drop, suspension, gel, ointment, cream or powder. Administration of the composition may also take place using a nasal tampon or nasal sponge.
[0102] For topical administration, suitable formulations may include biocompatible oil, wax, gel, powder, polymer, or other liquid or solid carriers. Such formulations may be administered by applying directly to affected tissues, for example, a liquid formulation to treat infection of conjunctival tissue can be administered dropwise to the subject's eye, or a cream formulation can be administered to the skin.
[0103] Rectal administration includes administering the pharmaceutical compositions into the rectum or large intestine. This can be accomplished using suppositories or enemas.
Suppository formulations can easily be made by methods known in the art. For example, suppository formulations can be prepared by heating glycerin to about 120 °C, dissolving the pharmaceutical composition in the glycerin, mixing the heated glycerin after which purified water may be added, and pouring the hot mixture into a suppository mold.
[0104] Transdermal administration includes percutaneous absorption of the composition through the skin. Transdermal formulations include patches, ointments, creams, gels, salves and the like. [0105] In addition to the usual meaning of administering the formulations described herein to any part, tissue or organ whose primary function is gas exchange with the external environment, for purposes of the present invention, "pulmonary" will also mean to include a tissue or cavity that is contingent to the respiratory tract, in particular, the sinuses. For pulmonary administration, an aerosol formulation containing the active agent, a manual pump spray, nebulizer or pressurized metered-dose inhaler as well as dry powder formulations are contemplated. Suitable formulations of this type can also include other agents, such as antistatic agents, to maintain the disclosed compounds as effective aerosols.
[0106] A drug delivery device for delivering aerosols comprises a suitable aerosol canister with a metering valve containing a pharmaceutical aerosol formulation as described and an actuator housing adapted to hold the canister and allow for drug delivery. The canister in the drug delivery device has a head space representing greater than about 15% of the total volume of the canister. Often, the compound intended for pulmonary administration is dissolved, suspended or emulsified in a mixture of a solvent, surfactant and propellant. The mixture is maintained under pressure in a canister that has been sealed with a metering valve.
[0107] The disclosure also encompasses the treatment of a condition associated with a dysfunction in proteostasis in a subject comprising administering to said subject an effective amount of a disclosed compound that enhances, improves or restores proteostasis of a protein. Proteostasis refers to protein homeostasis. Dysfunction in protein homeostasis is a result of protein misfolding, protein aggregation, defective protein trafficking or protein degradation. For example, the disclosure contemplates administering a disclosed compound e.g., Formula (IVa), (Va), (IV), or (V) that corrects protein misfolding, reduces protein aggregation, corrects or restores protein trafficking and/or affects protein degradation for the treatment of a condition associated with a dysfunction in proteostasis. In some aspects, a disclosed compound e.g., Formula (IVa), (Va), (IV), or (V) that corrects protein misfolding and/or corrects or restores protein trafficking is administered. In cystic fibrosis, the mutated or defective enzyme is the cystic fibrosis transmembrane conductance regulator (CFTR). One of the most common mutations of this protein is AF508 which is a deletion (Δ) of three nucleotides resulting in a loss of the amino acid phenylalanine (F) at the 508th (508) position on the protein. As 15 000211
described above, mutated cystic fibrosis transmembrane conductance regulator exists in a misfolded state and is characterized by altered trafficking as compared to the wild type CFTR. Additional exemplary proteins of which there can be a dysfunction in proteostasis, for example that can exist in a misfolded state, include, but are not limited to, glucocerebrosidase, hexosamine A, aspartylglucsaminidase, a-galactosidase A, cysteine transporter, acid ceremidase, acid oc-L-fucosidase, protective protein, cathepsin A, acid β-glucosidase, acid β- galactosidase, iduronate 2-sulfatase, a-L-iduronidase, galactocerebrosidase, acid a - mannosidase, acid β -mannosidase, arylsulfatase B, arylsulfatase A, N-acetylgalactosamine-6- sulfate sulfatase, acid β -galactosidase, N-acetylglucosamine-1 -phosphotransferase, acid sphingmyelinase, NPC-1 , acid cc-glucosidase, β-hexosamine B, heparin N-sulfatase, a -N- acetylglucosaminidase, a -glucosaminide N-acetyltransferase, N-acetylglucosamine-6-sulfate sulfatase, a -N-acetylgalactosaminidase, a -neuramidase, β -glucuronidase, β-hexosamine A and acid lipase, polyglutamine, a -synuclein, TDP-43, superoxide dismutase (SOD), Αβ peptide, tau protein, transthyretin and insulin. The compounds of Formula (IVa), (Va), (IV), or (V) can be used to restore proteostasis (e.g., correct folding and/or alter trafficking) of the proteins described above.
[0108] Protein conformational diseases encompass gain of function disorders and loss of function disorders. In one embodiment, the protein conformational disease is a gain of function disorder. The terms "gain of function disorder," "gain of function disease," "gain of toxic function disorder" and "gain of toxic function disease" are used interchangeably herein. A gain of function disorder is a disease characterized by increased aggregation-associated
proteotoxicity. In these diseases, aggregation exceeds clearance inside and/or outside of the cell. Gain of function diseases include, but are not limited to, neurodegenerative diseases associated with aggregation of polyglutamine, Lewy body diseases, amyotrophic lateral sclerosis, transthyretin-associated aggregation diseases, Alzheimer's disease, Machado-Joseph disease, cerebral B-amyloid angiopathy, retinal ganglion cell degeneration, tauopathies (progressive supranuclear palsy, corticobasal degeneration, frontotemporal lobar degeneration), cerebral hemorrhage with amyloidosis, Alexander disease, Serpinopathies, familial amyloidotic neuropathy, senile systemic amyloidosis, ApoAI amyloidosis, ApoAII amyloidosis, ApoAIV amyloidosis, familial amyloidosis of the Finnish type, lysozyme amyloidosis, fibrinogen amyloidosis, dialysis amyloidosis, inclusion body myositis/myopathy, cataracts, medullary thyroid carcinoma, cardiac atrial amyloidosis, pituitary prolactinoma, hereditary lattice corneal dystrophy, cutaneous lichen amyloidosis, corneal lactoferrin amyloidosis, corneal lactoferrin amyloidosis, pulmonary alveolar proteinosis, odontogenic tumor amyloid, seminal vesical amyloid, sickle cell disease, critical illness myopathy, von Hippel-Lindau disease,
spinocerebellar ataxia 1, Angelman syndrome, giant axon neuropathy, inclusion body myopathy with Paget disease of bone, frontotemporal dementia (IBMPFD) and prion diseases. Neurodegenerative diseases associated with aggregation of polyglutamine include, but are not limited to, Huntington's disease, dentatorubral and pallidoluysian atrophy, several forms of spino-cerebellar ataxia, and spinal and bulbar muscular atrophy. Alzheimer's disease is characterized by the formation of two types of aggregates: extracellular aggregates of Αβ peptide and intracellular aggregates of the microtubule associated protein tau. Transthyretin- associated aggregation diseases include, for example, senile systemic amyloidoses and familial amyloidotic neuropathy. Lewy body diseases are characterized by an aggregation of a- synuclein protein and include, for example, Parkinson's disease, Lewy body dementia (LBD) and multiple system atrophy (SMA). Prion diseases (also known as transmissible spongiform encephalopathies or TSEs) are characterized by aggregation of prion proteins. Exemplary human prion diseases are Creutzfeldt-Jakob Disease (CJD), Variant Creutzfeldt-Jakob Disease, Gerstmann-Straussler-Scheinker Syndrome, Fatal Familial Insomnia and Kuru. In another embodiment, the misfolded protein is alpha-1 anti-trypsin.
[0109] In a further embodiment, the protein conformation disease is a loss of function disorder. The terms "loss of function disease" and "loss of function disorder" are used interchangeably herein. Loss of function diseases are a group of diseases characterized by inefficient folding of a protein resulting in excessive degradation of the protein. Loss of function diseases include, for example, lysosomal storage diseases. Lysosomal storage diseases are a group of diseases characterized by a specific lysosomal enzyme deficiency which may occur in a variety of tissues, resulting in the build-up of molecules normally degraded by the deficient enzyme. The lysosomal enzyme deficiency can be in a lysosomal hydrolase or a protein involved in the lysosomal trafficking. Lysosomal storage diseases include, but are not limited to, aspartylglucosaminuria, Fabry's disease, Batten disease, Cystinosis, Farber, Fucosidosis, Galactasidosialidosis, Gaucher's disease (including Types 1, 2 and 3), Gm l gangliosidosis, Hunter's disease, Hurler-Scheie's disease, Krabbe's disease, oc-Mannosidosis, β-Mannosidosis, Maroteaux-Lamy's disease, Metachromatic Leukodystrophy, Morquio A syndrome, Morquio B syndrome, Mucolipidosis II, Mucolipidosis III, Neimann-Pick Disease (including Types A, B and C), Pompe's disease, Sandhoff disease, Sanfilippo syndrome (including Types A, B, C and D), Schindler disease, Schindler-Kanzaki disease, Sialidosis, Sly syndrome, Tay-Sach's disease and Wolman disease.
[0110] In another embodiment, the disease associated with a dysfunction in proteostasis is a cardiovascular disease. Cardiovascular diseases include, but are not limited to, coronary artery disease, myocardial infarction, stroke, restenosis and arteriosclerosis. Conditions associated with a dysfunction of proteostasis also include ischemic conditions, such as,
ischemia/reperfusion injury, myocardial ischemia, stable angina, unstable angina, stroke, ischemic heart disease and cerebral ischemia.
[0111] In yet another embodiment, the disease associated with a dysfunction in proteostasis is diabetes and/or complications of diabetes, including, but not limited to, diabetic retinopathy, cardiomyopathy, neuropathy, nephropathy, and impaired wound healing.
[0112] In a further embodiment, the disease associated with a dysfunction in proteostasis is an ocular disease including, but not limited to, age-related macular degeneration (AMD), diabetic macular edema (DME), diabetic retinopathy, glaucoma, cataracts, retinitis pigmentosa (RP) and dry macular degeneration.
[0113] In yet additional embodiments, a disclosed method is directed to treating a disease associated with a dysfunction in proteostasis, wherein the disease affects the respiratory system or the pancreas. In certain additional embodiments, a contemplated method encompass treating a condition selected from the group consisting of polyendocrinopathy hyperinsulinemia, diabetes mellitus, Charcot-Marie Tooth syndrome, Pelizaeus-Merzbacher disease, and
Gorham's Syndrome. [0114] Additional conditions associated with a dysfunction of proteostasis include hemoglobinopathies, inflammatory diseases, intermediate filament diseases, drug-induced lung damage and hearing loss. For example, provided herein are methods for the treatment of hemoglobinopathies (such as sickle cell anemia), an inflammatory disease (such as
inflammatory bowel disease, colitis, ankylosing spondylitis), intermediate filament diseases (such as non-alcoholic and alcoholic fatty liver disease) and drug induced lung damage (such as methotrexate-induced lung damage). In another embodiment, methods for treating hearing loss, such as noise-induced hearing loss, aminoglycoside-induced hearing loss, and cisplatin- induced hearing loss comprising administering a disclosed compound are provided.
[0115] Additional contemplated conditions include those associated with a defect in protein trafficking and that can be treated according to disclosed methods include: PGP mutations, hERG trafficking mutations, nephrongenic diabetes insipidus mutations in the arginine- vasopressin receptor 2, persistent hyperinsulinemic hypoglycemia of infancy (PHHl) mutations in the sulfonylurea receptor 1, and a lAT.
[0116] The invention is illustrated by the following examples which are not meant to be limiting in any way.
EXEMPLIFICATION
[0117] The compounds described herein can be prepared in a number of ways based on the teachings contained herein and synthetic procedures known in the art. In the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be chosen to be the conditions standard for that reaction, unless otherwise indicated. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed. Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated. The starting materials for the examples are either commercially available or are readily prepared by standard methods from known materials. At least some of the compounds identified as "intermediates" herein are contemplated as compounds of the invention. -(2-methoxyethyl)-5-phenyl-lH-pyrazol -3-carboxamide
Figure imgf000050_0001
[0118] A solution of 5-phenyl-lH-pyrazole-3-carboxylic acid (0.15 g, 0.79 mmol) in THF (10 mL), 2-methoxy-ethylamine (0.09 g, 1.18 mmol), EDC.HC1 (0.304 g, 1.59 mmol) and HOBt (0.214 g, 1.59 mmol) was stirred for 18 h at room temperature. Voiatiles were removed under vacuum, poured in ice-water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was dried over anhydrous Na2S04 and concentrated under reduced pressure to get a brown liquid. The crude residue was purified by combiflash using 20% MeOH in DCM to give the product (0.15 g, 78.9%) as off white solid; Ή NMR (400 MHz, CDC ): δ 12.01 (br, I H), 8.80 (br, IH), 7.61 -7.59 (d, J=7.4 Hz, 2H), 7.46-7.43 (t, 2H), 7.39- 7.36 (t, I H), 7.10 (s, I H), 3.75-3.73 (m, 2H), 3.70-3.63 (m, 2H), 3.46 (s, 3H); LC-MS: [M+H]+ 246.2; HPLC purity 99.82% at 220 nm and 99.82% at 254 nm.
[0119] Using above method the following compounds were synthesized using respective amine
Example 2: 5-phenyl-N-((tetrahydrofuran-2-yl)methyl)-lH-pyrazole-3-carboxamide
Figure imgf000050_0002
[0120] Yield (0.14 g,63.6 %) as off white solid; Ή NMR (400 MHz, CDC13): δ 12.19 (br, I H), 8.56 (br, I H), 7.62 -7.60 (d, J= 7.4 Hz, 2H), 7.46-7.42 (t, 2H), 7.38-7.35 (t, I H), 7.08 (s, I H), 4.22-4.20 (m, I H), 3.99-3.93 (m, I H), 3.86-3.81 (m, I H), 3.76-3.70 (m, IH), 3.59-3.54 (m, IH), 2.1 1 -2.04 (m, I H), 1.98-1.91 (m, 2H), 1 .75-1.70 (m, I H); LC-MS: [M+H]+ 271.8; HPLC purity 99.05 % at 220 nm and 98.60 % at 254 nm.
Example 3: N-(2-morpholinoethyl)-5-phenyl-lH-pyrazole-3-carboxamide
Figure imgf000051_0001
[0121] Yield (0.15 g,62.50 %) as off white solid; Ή NMR (400 MHz, CDC13): δ 10.89 (br, 1H), 7.62 -7.60 (d, J= 7.4 Hz, 2H), 7.45-7.42 (t, 2H), 7.39-7.35 (t, lH), 7.26 (br, 1 H), 7.00 (s, 1 H), 3.72-3.70 (m, 4H), 3.59-3.54 (m, 2H), 2.61 -2.58 (t, 2H), 2.50 (m, 4H); LC-MS: [M+H]+ 301.2; HPLC purity 99.68% at 220 nm and 99.66% at 254 nm.
Example 4: N-(3-(lH-imidazol-l-yl)propyl)-5-phenyl-lH-pyrazole-3-carboxamide
Figure imgf000051_0002
[0122] Yield (0.145 g,57.31 %) as off white solid; Ή NMR (400 MHz, CDC13): δ 7.64 - 7.62 (d, J= 7.32 Hz, 3H), 7.45-7.42 (t, 2H), 7.39-7.35 (t, 1H), 7.09 (s, 1H), 7.05 (s, 1H), 6.98 (s, 1H), 4.08-4.05 (m, 2H), 3.47-342 (m, 2H), 2.16-2.09 (m, 2H); LC-MS: [M+H]+ 296.2; HPLC purity 99.85% at 220 nm and 99.75% at 254 nm.
Example 5: CFTR activity assays
. Ussing measurements [0123] As discussed above, Ussing measurements are used to measure CFTR activity. In this method, primary lung epithelial cells (hBEs) homozygous for the Cystic Fibrosis-causing AF508 mutation are differentiated for a minimum of 4 weeks in an air-liquid interface on Snap Well filter plates prior to the Ussing measurements. Cells are apically mucus-washed for 30 minutes prior to treatment with compounds. The basolateral media is removed and replaced with media containing the compound of interest diluted to its final concentration from DMSO stocks. Treated cells are incubated at 37 °C and 5% C02 for 24 hours. At the end of the treatment period, the cells on filters are transferred to the Ussing chamber and equilibrated for 30 minutes. The short-circuit current is measured in voltage clamp-mode (Vhoia = mV), and the entire assay is conducted at a temperature of 36 °C -36.5 °C. Once the voltages stabilized, the chambers are clamped, and data is recorded by pulse readings every 5 seconds. Following baseline current stabilization, the following additions can be applied and the changes in current and resistance of the cells can be monitored:
1. Benzamil to the apical chamber to inhibit ENaC sodium channel.
2. Forskolin to both chambers to activate AF508-CFTR by phosphorylation.
3. Genistein to both chambers to potentiate AF508-CFTR channel opening.
4. CFTRinh- 172 to the apical chamber to inhibit AF508-CFTR CI- conductance.
[0124] The inhibitable current (that current that is blocked by CFTRinh-172) is measured as the specific activity of the AF508-CFTR channel, and increases in response to compound in this activity over that observed in vehicle-treated samples are identified as the correction of AF508-CFTR function imparted by the compound tested.
/. hBE Equivalent Current (Ieq) Assay
[0125] Primary lung epithelial cells homozygous for the Cystic Fibrosis-causing AF508 mutation were differentiated for a minimum of 4 weeks in an air-liquid interface on Costar 24 well HTS filter plates prior to the equivalent current (Ieq) measurements. Cells were apically mucus-washed for 30 minutes 24 h prior to treatment with compounds. The basolateral media was removed and replaced with media containing the compound of interest diluted to its final concentration from DMSO stocks. Treated cells were incubated at 37 °C and 5% C02 for 24 hours. At the end of the treatment period, the media was changed to the Ieq experimental solution for 30 minutes before the experiment and plates are maintained in a C02-free incubator during this period. The plates containing the cells were then placed in pre-warmed heating blocks at 36 °C±0.5 for 15 minutes before measurements are taken. The transepithelial voltage (VT) and conductance (GT) were measured using a custom 24 channel current clamp (TECC- 24) with 24 well electrode manifold. The Ieq assay measurements were made following additions with standardized time periods:
1. The baseline VT and G values were measured for approximately 20 minutes.
2. Benzamil was added to block ENaC for 15 minutes.
3. Forskolin plus VX-770 were added to maximally activate AF508-CFTR for 27 minutes. 4. Bumetanide was added to inhibit the NaK2Cl cotransporter and shut-off secretion of chloride.
[0126] The activity data captured was the area under the curve (AUC) for the traces of the equivalent chloride current. The AUC was collected from the time of the forskolin/VX-770 addition until the inhibition by bumetanide addition. Correction in response to compound treatment was scored as the increase in the AUC for compound-treated samples over that of vehicle-treated samples. The results are shown below in Table 2. The results are shown below in Table 2. (** indicates activity >200% of VX-809 (1 uM) with compound at 10 uM and VX- 809 at 1 uM; * indicates activity 100-200% of VX-809 (1 uM) with compound at 10 uM and VX-809 at 1 uM. m indicates activity >200% of VX-809 (3 uM) with compound at 10 uM and VX-809 at 3 uM; * indicates acti vity 100-200% of VX-809 (3 uM) with compound at 10 uM and VX-809 at 3 uM.
Table 2
Figure imgf000053_0001
Figure imgf000054_0001
N-NH H
[0127] While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.
[0128] Example 6
/'. Ussing measurements
[0129] As discussed above, Ussing measurements can be used to measure CFTR activity. In this method, primary lung epithelial cells (hBEs) with a Cystic fibrosis causing class I mutation are differentiated for a minimum of 4 weeks in an air-liquid interface on Snap Well™ filter plates prior to the Ussing measurements. Cells are apically mucus-washed for 30 minutes prior to treatment with compounds. The basolateral media is removed and replaced with media containing the compound of interest diluted to its final concentration from DMSO or aqueous stocks. Treated cells are incubated at 37 °C and 5% C02 for 24 hours. At the end of the treatment period, the cells on filters are transferred to the Ussing chamber and equilibrated for 30 minutes. The short-circuit current is measured in voltage clamp-mode ( hoid = 0 mV), and the entire assay is conducted at a temperature of 36 °C -36.5 °C. Once the voltages stabilize, the chambers are clamped, and data are recorded by pulse readings every 5 seconds. Following baseline current stabilization, the following additions are applied and the changes in current and resistance of the cells are monitored: 1. Benzamil to the apical chamber to inhibit ENaC sodium channel.
2. Forskolin to both chambers to activate AF508-CFTR by phosphorylation.
3. Ivacaftor or Genistein to the apical chamber to potentiate AF508-CFTR channel
opening.
4. CFTRinh-172 to the apical chamber to inhibit AF508-CFTR CI- conductance.
[0130] The forskolin-sensitive current and inhibitable current (that potentiated current that is blocked by CFTRinh-172) are measured as the specific activity of the AF508-CFTR channel, and increase in response to compound in this activity over that observed in vehicle-treated samples are identified as the correction of AF508-CFTR function imparted by the compound tested.
[0131] Example 7 . Ussing measurements
[0132] As discussed above, Ussing measurements can be used to measure CFTR activity. In this method, primary lung epithelial cells (hBEs) with a Cystic Fibrosis-causing class III mutation are differentiated for a minimum of 4 weeks in an air-liquid interface on Snap Well™ filter plates prior to the Ussing measurements. Cells are apically mucus-washed for 30 minutes prior to treatment with compounds. The basolateral media is removed and replaced with media containing the compound of interest diluted to its final concentration from DMSO stocks. Treated cells are incubated at 37 °C and 5% C02 for 24 hours. At the end of the treatment period, the cells on filters are transferred to the Ussing chamber and equilibrated for 30 minutes. The short-circuit current is measured in voltage clamp-mode (Vhoid = 0 mV), and the entire assay is conducted at a temperature of 36 °C -36.5 °C. Once the voltages stabilize, the chambers are clamped, and data is recorded by pulse readings every 5 seconds. Following baseline current stabilization, the following additions are applied and the changes in current and resistance of the cells is monitored:
1. Benzamil to the apical chamber to inhibit ENaC sodium channel. 2. Forskolin to both chambers to activate AF508-CFTR by phosphorylation.
3. VX-770 or Genistein to the apical chamber to potentiate AF508-CFTR channel opening.
4. CFTRinh-172 to the apical chamber to inhibit AF508-CFTR CI- conductance.
[0133] The forskolin-sensitive current and inhibitable current (that potentiated current that is blocked by CFTRinh-172) are measured as the specific activity of the AF508-CFTR channel, and increase in response to compound in this activity over that observed in vehicle-treated samples are identified as the correction of AF508-CFTR function imparted by the compound tested. [0134] Example 8
/'. Ussing measurements
[0135] As discussed above, Ussing measurements can be used to measure CFTR activity. In this method, primary lung epithelial cells (hBEs) with a Cystic Fibrosis-causing class V mutation are differentiated for a minimum of 4 weeks in an air-liquid interface on
Snap Well™ filter plates prior to the Ussing measurements. Cells are apically mucus-washed for 30 minutes prior to treatment with compounds. The basolateral media is removed and replaced with media containing the compound of interest diluted to its final concentration from DMSO stocks. Treated cells are incubated at 37 °C and 5% C02 for 24 hours. At the end of the treatment period, the cells on filters are transferred to the Ussing chamber and equilibrated for 30 minutes. The short-circuit current is measured in voltage clamp-mode (Vhoid = 0 mV), and the entire assay is conducted at a temperature of 36 °C -36.5 °C. Once the voltages stabilize, the chambers are clamped, and data is recorded by pulse readings every 5 seconds. Following baseline current stabilization, the following additions are applied and the changes in current and resistance of the cells is monitored:
1. Benzamil to the apical chamber to inhibit ENaC sodium channel.
2. Forskolin to both chambers to activate AF508-CFTR by phosphorylation. 3. VX-770 or Genistiein to the apical chamber to potentiate AF508-CFTR channel opening.
4. CFTRinh-172 to the apical chamber to inhibit AF508-CFTR CI- conductance.
[0136] The forskolin-sensitive current and inhibitable current (that potentiated current that is blocked by CFTRinh-172) are measured as the specific activity of the AF508-CFTR channel, and increases in response to compound in this activity over that observed in vehicle-treated samples are identified as the correction of AF508-CFTR function imparted by the compound tested. ii. hBE Equivalent Current (Ieq) Assay
[0137] Primary lung epithelial cells homozygous for the Cystic Fibrosis-causing AF508 mutation are differentiated for a minimum of 4 weeks in an air-liquid interface on Costar 24 well HTS filter plates prior to the equivalent current (Ieq) measurements. Cells are apically mucus-washed for 30 minutes 24 h prior to treatment with compounds. The basolateral media is removed and replaced with media containing the compound of interest diluted to its final concentration from DMSO stocks. Treated cells are incubated at 37 °C and 5% C02 for 24 hours. At the end of the treatment period, the media is changed to the Ieq experimental solution for 30 minutes before the experiment and plates are maintained in a C02-free incubator during this period. The plates containing the cells are then placed in pre-warmed heating blocks at 36 °C±0.5 for 15 minutes before measurements are taken. The transepithelial voltage (VT) and conductance (GT) are measured using a custom 24 channel current clamp (TECC-24) with 24 well electrode manifold. The Ieq assay measurements are made following additions with standardized time periods:
1. The baseline VT and GT values are measured for approximately 20 minutes. 2. Benzamil is added to block ENaC for 15 minutes.
3. Forskolin plus VX-770 (ivacaftor) are added to maximally activate AF508-CFTR for 27 minutes. 4. Bumetanide is added to inhibit the NaK2Cl cotransporter and shut-off secretion of chloride.
[0138] The activity data captured is the area under the curve (AUC) for the traces of the equivalent chloride current. The AUC is collected from the time of the forskoIin/VX-770 addition until the inhibition by bumetanide addition. Correction in response to compound treatment is scored as the increase in the AUC for compound-treated samples over that of vehicle-treated samples.
INCORPORATION BY REFERENCE
[0139] All publications and patents mentioned herein, including those items listed below, are hereby incorporated by reference in their entirety for all purposes as if each individual publication or patent was specifically and individually incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.
EQUIVALENTS
[0140] While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.
[0141] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention.

Claims

What is claimed is:
A compound represented by formula IV
Figure imgf000059_0001
and pharmaceutically acceptable salts, stereoisomers, and prodrugs thereof, wherein:
Xi is CH or N; wherein when Xi is N, Rz is not present and the nitrogen with Rz has a double bond with the adjacent N and there is a single bond between Xi and the adjacent N, and when Xi is CH, Xi has a double bond with the nitrogen adjacent, and Rz is selected from the group consisting of H, and Ci-3alkyl, and the nitrogen with Rz has a single bond with the adjacent N;
X3 is selected from the group consisting of O, S, and NRht,;
pp for each occurrence is selected from the group consisting of 1 , 2, or 3; R] I is independently selected for each occurrence from the group consisting of hydrogen, halogen, and (optionally substituted by one, two or three halogens);
Li is selected from the group consisting of Ci.6alkylene, C3-6cycloalkylene, C3.
6cycloalkylene-Ci-4alkylene, Ci-3alkylene-NRhh-S(0)w-, - Ci-3alkylene-S(0)w-NRhh-, C3- 6cycloalkylene-Co-2aIkyIene-S(0)w-NRhh, and C3-6cycloalkylene- Co-2alkylene NRht,-S(0)w-, wherein Lt may be optionally substituted by one, two or three substituents selected from the group consisting of halogen, hydroxy 1, and Ci-3alkyl (optionally substituted by one, two or three substituents each selected independently from Rff);
R44 is selected from the group consisting of H, halogen, hydroxy 1, Ci-3alkoxy, heterocycle, and a 5-6 membered monocyclic or 8-10 membered bicyclic heteroaryl having one, two or three heteroatoms each selected from O, N, and S; wherein the heterocycle and the heteroaryl may be optionally substituted by one or two substituents each selected independently from Rgg;
Rfr is selected for each occurrence from group consisting of halogen, hydroxyl, Ct. 4alkyl, C alkyoxy, C2.4alkenyl, C3-6cycloalkyl, -NR'R", -NR'-S(0)w-Ci-3alkyl, S(0)w- NR'R", and -S(0)w-Ci-3alkyl, where w is 0, 1 , or 2, wherein Ci.4alkyl, Ci-4alkyoxy, C2-4alkenyl and C3-6cycloalkyl may be optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, -NR'R", -NR'-S(0)w- C,.3alkyl, S(0)w-NR'R", and -S(0)w-Ci-3alkyl;
Rgg is selected for each occurrence from group consisting of halogen, hydroxyl, Q. 6alkyl, Ci-6aIkyoxy, C2-6alkenyl, C3.6cycloalkyl, -NR'R", -NR'-S(0)w-C,-3alkyl, S(0)w- NR'R", and -S(0)w-Ci-3alkyl, where w is 0, 1 , or 2, wherein Ci-6alkyl, Ci-ealkyoxy, C2-6alkenyl and C3-6cycloalkyl may each be optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, Ci-6alkyl, Q-ealkoxy, hydroxyl, C(0)OH, -C(0)OC|.6alkyl, -0-C3-6cycloalkyl, -O-heterocycle, -O-heteroaryl, -O-phenyl, - NR'R", -NR'-S(0)w-C1 -3alkyl, S(0)w-NR'R", and -S(0)w-Ci-3alkyl;
w is 0, 1 or 2; and
Rhh is selected for each occurrence from the group consisting of H, Q-ealkyl and C3- ecycloalkyl.
2. The compound of claim 1 , wherein Li is C|-3alkylene or C3-5cycloalkylene.
3. The compound of claim 1 or 2, represented by:
Figure imgf000061_0001
wherein qq is 0 or 1.
4. The compound of any one of claims 1-3, represented by:
Figure imgf000061_0002
5. The compound of any one of claims 1-4, wherein R44 is selected from the group consisting of pyrrolidinyl, piperidinyl, tetrahydropyranyl, and tetrahydrofuranyl.
6. The compound of any one of claims 1-4, wherein R44 is selected from the group consisting of:
Figure imgf000062_0001
wherein X independently for each occurrence is selected from the group consisting of O, S, NRhh, C, C(R88), and C(R88)(R99); X2 independently for each occurrence is selected from the group consisting of O, S and NRhhi R" is H or C]-4alkyl, each R66, R77, Rss and R99 is independently selected for each occurrence from H and Rgg, and n is 0, 1 , 2, or 3.
7. The compound of claim 6, wherein each ¾6, R77, Rss and R99 is independently selected for each occurrence from the group consisting of hydrogen, halogen, hydroxyl, Ch alky!, C3-6 cycloalkyl, and heterocycle, wherein Ci-6 alkyl, C3-6 cycloalkyl, and heterocycle are optionally substituted by one, two or three substituents each independently selected from the group consisting of hydroxyl, C) -6 alkyl, Ci_6 alkoxy (optionally substituted by C3-6cycloalkyl, heterocycle,
Figure imgf000062_0002
and Ci-2alkyl- C3.6cycloalkyl) , -S(0)w-Ci-3 alkyl (w is 0, 1 , or 2) and -NR'S(0)2Ci-6 alkyl; and
R' is independently selected for each occurrence from H and C alkyl.
8. The compound of any one of claims 1 -7, wherein pp is 0, 1 or 2, and Rn is selected from H, F, or methyl.
9. A compound having the Formula (IVa) or the Formula (Va):
Figure imgf000063_0001
(Va);
or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein:
Ri is selected from the group consisting of:
Figure imgf000063_0002
R2 is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl;
R3a is selected from the group consisting of hydrogen, optionally substituted Ci-Ci0 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-Ci2 cycloalkyl, optionally substituted C3-Ci2 cycloalkenyl, optionally substituted aryl, halo, ORc, NR^Rd, C(0)ORc, N02, CN, C(0)Rc, C(0)C(0)Rc, C(0)NRdRd, NR<iC(0)Rc, NRdS(0)nRc, N(Rd)(COORc), NR<jC(0)C(0)Rc, NRdC(0)NRdR<j, NRdS^NRdRd, NRdStO Rc, S(0)nRc, 8(0)„Ν¾¾, OC(0)ORc, (C=NRd)Rc, optionally substituted heterocyclic and optionally substituted heteroaryl;
R4a is selected from the group consisting of hydrogen, optionally substituted C|-Cio alkyl, optionally substituted C2-Cio alkenyl, optionally substituted C2-Cio alkynyl, optionally substituted C3-Ci2 cycloalkyl, optionally substituted C3-Ci2 cycloalkenyl, optionally substituted aryl, halo, ORc, S(0)nRc, NR^Rd, C(0)ORc, N02, CN, C(0)Rc, C(0)C(0)Rc, C(0)NRdRd, NRdC(0)Rc, NRoS(0)Rc, N(R<J)(COORc), NRdC(0)C(0)Rc, NRdC(0)NRdRd, NRdS(0)nRd d, NRdS(0)nRc, S(0)NRdR<j, OC(0)ORc,
Figure imgf000064_0001
optionally substituted heterocyclic and optionally substituted heteroaryl;
R4b is selected from the group consisting of hydrogen, optionally substituted C]-Cio alkyl, optionally substituted C2-Cio alkenyl, optionally substituted C2-Ci0 alkynyl, optionally substituted C3-Ci2 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted aryl, optionally substituted heterocyclic and optionally substituted heteroaryl;
Ra is selected from the group consisting of hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-Cio alkynyl, optionally substituted C3-Ci2 cycloalkyl, optionally substituted C3-C] 2 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, C(0)ORc, C(0)Rc, C(0)C(0)Rc and S(0)nRc;
or alternatively, Ra and the nitrogen atom to which it is attached is taken together with an adjacent C(Rbi)(Rbi) or C(Rb2)(Rb2) to form an optionally substituted, 4- to 12-membered heterocyclic ring containing one or more ring nitrogen atoms, wherein said heterocyclic ring optionally contains one or more ring heteroatoms selected from oxygen and sulfur;
each Rbi and Rb2 is independently selected from the group consisting of hydrogen, optionally substituted Ci-Cio alkyl, optionally substituted C2-Ci0 alkenyl, optionally substituted C2-Cio alkynyl, optionally substituted C3-Ci2 cycloalkyl, optionally substituted C3-Ci2 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, ORc, NRdRd, 0(0)0^, N02, CN, C(0)Rc, C(0)C(0)Rc,
C(0)NR<iRd, NRdC(0)Rc, NRdS(0)nRc, Ν(¾)(∞0¾), RdC^CiO)^, Ν¾^0)Ν¾¾,
Figure imgf000064_0002
OC(0)ORc and (C=NRd)Rc; or alternatively, two geminal Rbi groups or two geminal Rt>2 groups and the carbon to which they are attached are taken together to form a C(O) group, or yet alternatively, two geminal Rbi groups or two geminal Rb2 groups are taken together with the carbon atom to which they are attached to form a spiro C3-C12 cycloalkyl, a spiro C3-Ci2 cycloalkenyl, a spiro heterocyclic, a spiro aryl or spiro heteroaryl, each optionally substituted;
Y is selected from the group consisting of S(0)n,, NRo, NRdS(0)n, NRdS(0)nNRd, NRdC(O), NRdC(0)0, NR<,C(0)C(0), NRdC(0)NR<j, S(0)nNRd, and O;
each Rc is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-Cio alkynyl, optionally substituted C3-Ci2 cycloalkyl, optionally substituted C3-Ci2 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;
each Rd is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C10 alkyl, optionally substituted C2-Cio alkenyl, optionally substituted C2-Cio alkynyl, optionally substituted C 1 -C10 alkoxy, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-Ci2 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl; or two geminal Rd groups are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic or an optionally substituted heteroaryl;
k is 0 or 1 ;
m is 0, 1, 2, 3, 4, or 5;
each n is independently 0, 1 or 2.
10. The compound of claim 9, wherein m is 0, 1 or 2.
1 1. The compound of claim 9 or 10, wherein m is 0.
12. The compound of claim 9 or 10, wherein m is 1.
13. The compound of any one claims 9-12, wherein R3a is hydrogen.
14. The compound of any one of claims 9-13, wherein Ra is hydrogen or C1 -C4 alkyl (optionally substituted by 1 , 2 or 3 halogens).
15. The compound of any one of claims 9-14, wherein Ra is hydrogen.
16. The compound of any one claims 9-15, wherein each of Rbi and Rb2 is independently selected from of hydrogen, hydroxyl,
Figure imgf000066_0001
(optionally substituted by one, two or three substituents independently selected from halogen and hydroxyl) and C1-C4 alkyl (optionally substituted by one, two or three substituents independently selected from halogen, hydroxyl, and Ci^alkoxy).
17. The compound of any one of claims 9-16, wherein R2 is selected from the group consisting of phenyl and a 5-6 membered heteroaryl having one or two heteroatoms each selected from N, S, and O, wherein R2 is optionally substituted by one or two substituents each independently selected from the group consisting of halogen, and C1-C4 alkyl (optionally substituted by one, two or three halogens.
18. The compound of any one of claims 9-17, wherein R2 is phenyl.
19. The compound of any one of claims 9-18, wherein R2 is phenyl is substituted with one or two R5_ wherein each R5 is independently selected from the group consisting of optionally substituted C 1 -C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-Cio alkynyl, and halo.
20. The compound of any one of claims 9-17, wherein R2 is selected from the group consisting of optionally substituted thienyl, optionally substituted furanyl and optionally substituted pyridinyl.
21 . The compound of claim 19, wherein R2 is a para-substituted phenyl.
22. The compound of claim 19, wherein R2 is phenyl is substituted one or two R5, wherein each R5 is independently selected from the group consisting of optionally substituted C1 -C 10 alkyl, optionally substituted C2-Ci0 alkenyl, optionally substituted C2-Ci0 alkynyl, and halo.
23. The compound of any one of claims 9-22, wherein R4a is selected from the group consisting of optionally substituted Ci-C6 alkyl, optionally substituted C3-C7 cycloalkyl, phenyl, ORC, C(0)ORC, C(0)RC, optionally substituted heterocycle and optionally substituted heteroaryl, wherein Rc is selected, independently for each occurrence, from the group consisting of H and Ci-6alkyl.
24. The compound of any one of claims 9-22, wherein R4a is a heterocycle, or a 5-6 membered monocyclic or a 8- 10 membered bicyclic heteroaryl having one, two or three heteroatoms selected from N, S or O, wherein the heterocycle or heteroaryl are optionally substituted by one, two or three substituents independently selected for each occurrence from the group consisting of halogen, C].6alkyl (optionally substituted by one, two or three substituents each independently selected from halogen and hydroxyl), Ci-6alkoxy (optionally substituted by one, two or three halogens), hydroxyl, and NR^R^ wherein Rd is independently for each occurrence selected from H and
Figure imgf000067_0001
or the two R<jS taken together with the N to which they are attached form a heterocyclic ring.
25. The compound of any one of claims 9-22, wherein R4a is selected from the group consisting of:
Figure imgf000067_0002
wherein each X is independently O, S or NRg;
each Rg is independently selected from the group consisting of hydrogen, C1-C4 alky I, C3-C6 cycloalkyl, and
each R^ R7 and R8 is independently selected for each occurrence from the group consisting of hydrogen, Ci-C6 alkyl, C2-C6 alkenyl, C2-C 16 alkynyl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, phenyl, heterocycle, heteroaryl, halo, hydroxyl, carboxyl, ORc, NRdRd,
C(0)ORc, CN, C(0)Rc, wherein the C,-6alkyl, C2-C6 alkenyl, C2-C,6 alkynyl, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, phenyl, heterocycle, and heteroaryl of Re, R7 and R8 may each be optionally substituted by one, two or three substituents selected from halo, hydroxyl, Ci^alkyl and Ci_6alkoxy; Rc is C alkyl; and
Rd is independently for each occurrence selected from the group consisting of H and Cj. 4alkyl, or the two RjS taken together with the N to which they are attached form a heterocyclic ring.
26. The compound of claim 23, wherein R^ is an optionally substituted C3-C7 cycloalkyl.
27. The compound of claim 26, wherein R^ is an optionally substituted cyclopropyl or an optionally substituted cyclobutyl.
28. The compound of claim 26 or 27, wherein R4a is a C3-C7 cycloalkyl substituted with a substituent having the formula:
Figure imgf000068_0001
wherein:
each Rj, is independently selected from the group consisting of hydrogen, halo, optionally substituted Ci-Qo alkyl, and optionally substituted C3-C6 cycloalkyl, or two geminal Rb groups are independently taken together with the carbon atom to which they are attached to form an optionally substituted heterocyclic or an optionally substituted heteroaryl;
R9 is selected from the group consisting of hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C2-Cio alkenyl, optionally substituted C2-Cio alkynyl, optionally substituted C3-Ci2 cycloalkyl, optionally substituted C3-Q2 cycloalkenyl, optionally substituted ary 1, halo, OR , NR<jRd, C(0)ORc, N02, CN, C(0)Rc, C(0)C(0)Rc, C(0)NRdRd, NRdC(0)Rc, RdS(0)nRc, NRd(COORc), NRdC(0)C(0)Rc, NRdC(0)NRdRd,
Figure imgf000068_0002
NRdS(0)nRc, S(0)nRc, S(0)nNRdRd, OC(0)ORc, (C=NRd)Rc, optionally substituted heterocyclic and optionally substituted heteroaryl;
p is 0, 1 , or 2;
and wherein the C3-C7 cycloalkyl is optionally further substituted.
29. The compound of any one of claims 23-26, wherein R4a is selected from the group consisting of:
Figure imgf000069_0001
; wherein each Rio is independently selected from the group consisting of hydrogen, optionally substituted CpCio alkyl, optionally substituted C2-Ci0 alkenyl, optionally substituted C2-Cio alkynyl, optionally substituted C3-Ci2 cycloalkyi, optionally substituted C3-Ci2 cycloalkenyl, optionally substituted aryl, halo, ORc, NRjRd, C(0)ORc, N02, CN, C(0)Rc, C(0)C(0)Rc, C(0)NRdRd, NRdC(0)Rc, NRdS(0)nRc, NRd(COORc), NRdC(0)C(0)Rc, NRdC^NRdRd, NRdS(0)nNRdRd, NRdSCOinRc, S(0)nRc, S(0)„NRdRd,
Figure imgf000069_0002
optionally substituted heterocyclic and optionally substituted heteroaryl; alternatively, two geminal Rio groups are taken together with the carbon atom to which they are attached to form a spiro C3- Ci2 cycloalkyi, a spiro C3-C|2 cycloalkenyl, a spiro heterocyclic, a spiro aryl or spiro heteroaryl, each optionally substituted; or yet alternatively, two vicinal Rio groups are taken together with the carbon atoms to which they are attached to form a fused, optionally substituted cyclic group selected from the group consisting of C4-C8 cycloalkyi, C4-C8 cycloalkenyl, 4- to 8-membered heterocyclic, aryl and heteroaryl, each optionally substituted; or further alternatively, two Rio groups attached to non-adjacent carbon atoms are taken together with the carbon atoms to which they are attached to form a bridged cyclic group selected from the group consisting of C4-C8 cycloalkyi, C4-C8 cycloalkenyl, and 4- to 8-membered heterocyclic, each optionally substituted;
each Rh is independently selected from the group consisting of hydrogen, halo, optionally substituted Q-Cio alkyl, and optionally substituted C3-C6 cycloalkyi, or two geminal Rb groups are independently taken together with the carbon atom to which they are attached to form an optionally substituted heterocyclic or an optionally substituted heteroaryl;
R9 is selected from the group consisting of hydrogen, optionally substituted Ci-Cio alkyl, optionally substituted C2-Cio alkenyl, optionally substituted C2-Cjo alkynyl, optionally substituted C3-Ci2 cycloalkyl, optionally substituted C3-C)2 cycloalkenyl, optionally substituted aryl, halo, ORc, NRjRd, C(0)ORc, N02, CN, C(0)Rc, C(0)C(0)Rc, C(0)NRdR<i, NR^CCO)^ NRaSCOJnRc- NRdCCOORc), NRdC(0)C(0)Rc, NRdC(0)NR<jR<j,
Figure imgf000070_0001
NRdS(0)„Rc, S(0)nRc, S(0)„NR<|Rd, OC(0)ORc, (C=NR<i)Rc, optionally substituted heterocyclic and optionally substituted heteroaryl;
p is 0, 1 , or 2.
30. The compound of any one of claims 9-29, wherein Y is S, S(0)2 or S(0)2NRd.
31. The compound of any one of claims 9-30, wherein R-tb is a heterocycle or a 5-6 membered monocyclic or a 8- 10 membered bicyclic heteroaryl having one, two or three heteroatoms selected from N, S or O, wherein the heterocycle or heteroaryl are optionally substituted by one, two or three substituents independently selected for each occurrence from the group consisting of halogen, Ci-6alkyl (optionally substituted by one, two or three substituents each independently selected from halogen and hydroxyl), C)-6alkoxy (optionally substituted by one, two or three halogens), hydroxyl, and RdRd wherein ¾ is independently for each occurrence selected from H and Ci-4alkyl, or the two RdS taken together with the N to which they are attached form a heterocyclic ring.
32. The compound of any one of claims 9-31, wherein R4b is selected from the group consisting of furanyl, pyridinyl, pyrazinyl, pyrazolyl, imidazolyl, isoxazolyl, triazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, thienyl, piperazinyl, and benzimidazolyl, each optionally substituted.
33. A compound selected from the group consisting of :
Figure imgf000070_0002
Figure imgf000071_0001
Figure imgf000072_0001
pharmaceutically acceptable salts thereof.
34. A pharmaceutical composition comprising a compound of any one of claims 1 to 33 and a pharmaceutically acceptable carrier or excipient.
35. The pharmaceutical composition of claim 34, wherein the composition further comprises at least one additional CFTR modulator.
36. The pharmaceutical composition of claim 34, wherein the composition further comprises at least two additional CFTR modulators.
37. A method of enhancing cystic fibrosis transmembrane conductance regulator (CFTR) activity in a subject in need thereof comprising administering to said subject an effective amount of a compound of any one of claims 1 to 33, or a pharmaceutical composition of any one claims 34 to 36.
38. The method of claim 37, wherein the activity of a mutant CFTR is enhanced.
39. The method of claim 38, wherein the mutant CFTR is selected from the group consisting AF508, S549N, G542X, G551 D, Rl 17H, N 1303K, W1282X, R553X, 621+1 G>T, 1717- lOA, 3849+lOkbOT, 2789+50A, 3120+1 OA, I507del, Rl 162X, 1898+lOA, 3659delC, G85E, Dl 152H, R560T, R347P, 2184insA, A455E, R334W, Q493X, and 2184delA CFTR.
40. The method of claim 39, wherein AF508 CFTR activity is enhanced.
41. The method of any one of claims 37 to 40, wherein the subject is suffering from a disease associated with decreased CFTR activity.
42. The method of claim 41, wherein the disease is selected from the group consisting of cystic fibrosis, congenital bilateral absence of vas deferens (CBAVD), acute, recurrent, or chronic pancreatitis, disseminated bronchiectasis, asthma, allergic pulmonary aspergillosis, chronic obstructive pulmonary disease (COPD), chronic sinusitis, dry eye disease, protein C deficiency, Α-β-lipoproteinemia, lysosomal storage disease, type 1 chylomicronemia, mild pulmonary disease, lipid processing deficiencies, type 1 hereditary angioedema, coagulation-fibrinolyis, hereditary hemochromatosis, CFTR-related metabolic syndrome, chronic bronchitis, constipation, pancreatic insufficiency, hereditary emphysema, Sjogren's syndrome, familial hypercholesterolemia, I-cell disease/pseudo-Hurler, mucopolysaccharidoses, Sandhof/Tay- Sachs, Crigler-Najjar type II, polyendocrinopathy/hyperinsulemia, Diabetes mellitus, Laron dwarfism, myleoperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1 , congenital hyperthyroidism, osteogenesis imperfecta, hereditary
hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI), neurophyseal DI, nephrogenic DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, Huntington's disease, spinocerebellar ataxia type I, spinal and bulbar muscular atrophy, dentatorubral pallidoluysian, myotonic dystrophy, hereditary Creutzfeldt-Jakob disease (due to prion protein processing defect), Fabry disease, and Straussler-Scheinker syndrome.
43. The method of claim 42, wherein the disease is cystic fibrosis.
44. The method of claim 43, wherein the subject is a human patient.
45. The method of claim 44, further comprising administering an additional CFTR modulator.
46. The method of claim 44, wherein at least two additional CFTR modulators are
administered.
47. The method of any one of claims 45 and 46, wherein at least one CFTR modulator is a CFTR corrector or potentiator.
48. The method of claim 47, wherein the CFTR corrector is selected from the group consisting of VX-809, VX-661 , VX-152, VX-440, GLPG 2665, GLPG-2222 and VX-983 and the CFTR potentiator is selected from the group consisting of GLPG- 1837, ivacaftor and genistein.
49. The method of claim 48, wherein one of the at least two additional therapeutic agents is a CFTR corrector and the other is a CFTR potentiator.
50. A method of identifying a candidate agent that increases CFTR activity, comprising: a) contacting a cell that expresses a CFTR protein with the candidate agent and a compound of any one of claims 1 to 33;
b) measuring the CFTR activity in the cell in the presence of the candidate agent and the compound of any one of claims 1 to 33; and c) comparing the CFTR activity to that in the absence of the test agent, wherein an increase in CFTR activity in the presence of the test agent indicates that the agent increases CFTR activity.
51. The method of claim 50, wherein the cell expresses a mutant CFTR protein.
52. The method of any one of claims 50 and 51 , wherein CFTR activity is measured by measuring chloride channel activity of the CFTR, and/or other ion transport activity.
53. The method of claim 52, wherein the method is high-throughput.
54. The method of any one of claims 50 to 53, wherein the candidate agent is a CFTR corrector or a CFTR potentiator.
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